Fused-ring pyridine derivative, process for producing the same, and use

ABSTRACT

The present invention provides a compound represented by the formula:  
                 
 
wherein R 1  is a 5- or 6-membered ring which may be substituted; 
 
     R 3  is a hydrogen atom, a lower alkyl group or a lower alkoxy group;  
     Z 1  is a 5- or 6-membered aromatic ring;  
     Z 2  is a group represented by -Z 2a -W 2 -Z 2b  wherein Z 2a  and Z 2b  are each O, S(O) m  (wherein m is 0, 1 or 2), an imino group, or a bond; and W 2  is an alkylene chain which may be substituted; n is an integer of 0 to 4;  
     Y is O, S(O) p  (wherein p is 0, 1 or 2), CH 2  or NR 4  (wherein R 4  is a hydrogen atom, a hydrocarbon group, a heterocyclic group, or an acyl group); and  
     R 2  is (1) an amino group, in which the nitrogen atom is converted to quaternary ammonium or oxide, (2) a nitrogen-containing heterocyclic group which may contain a sulfur atom or an oxygen atom as a ring-constituting atom, in which the nitrogen atom may be converted to a quaternary ammonium or an oxide, and the like, or a salt thereof. The compound has excellent CCR5 antagonist activity and is useful as a prophylactic and/or therapeutic medicine for HIV infection in human peripheral mononuclear blood cells, especially AIDS.

TECHNICAL FIELD

The present invention relates to a new cyclic compound having CCRantagonist activity, especially CCR5 antagonist activity, and to usethereof.

BACKGROUND ART

Recently, HIV (human immunodeficiency virus) protease inhibitors havebeen developed for the treatment of AIDS (acquired immune deficiencysyndrome). With combined use of the protease inhibitors with two HIVreverse transcriptase inhibitors which have been commonly used,treatment of AIDS has made remarkable progress. However, the treatmentof AIDS is still not efficient enough for the eradication of AIDS, anddevelopment of a new anti-AIDS medicine based on a different mechanismof action is desired.

As a receptor upon invasion of HIV into a target cell, CD4 has alreadybeen known. Recently, CCR5 as a second receptor of macrophage directedHIV and CXCR4 as a second receptor of T cell directed HIV, which areG-protein coupled chemokine receptors having a seven-transmembraneprotein structure, have been found, and these chemokine receptors areconsidered to play an essential role for infection and transmission ofHIV. As a matter of fact, it has been reported that a human havingresistance to HIV infection even after repeated exposures to the virushad a mutation in which CCR5 gene was deleted homozygously. Thus, theCCR5 antagonists have been expected to become a new anti-HIV medicine,and examples of synthesis of new anilide derivatives having CCR5antagonist activity have been reported in, for example, thebelow-mentioned patent applications such as Patent Document 1, PatentDocument 2, and Patent Document 3, while there has been no report of aCCR5 antagonist which has been commercialized as a therapeutic medicinefor AIDS. Further, a compound having CCR5 antagonist activity isdescribed to be useful as a prophylactic and/or therapeutic medicine forAIDS in the below-mentioned Patent Document 4, but the compound has adifferent structure from the compound of the present invention.

Patent Document 1: WO99/32100

Patent Document 2: Japanese Patent Application No. 10-234388

Patent Document 3: Japanese Patent Application No. 10-363404

Patent Document 4: JP-A No. 2001-026586

DISCLOSURE OF THE INVENTION

The present invention is to provide a new bicyclic compound that isuseful as a prophylactic and/or therapeutic medicine for HIV infection,especially AIDS, due to its CCR antagonist activity, especially CCR5antagonist activity.

The present inventors have intensively studied compounds having CCR5antagonist activity and found a compound of the following formula (I) ora salt thereof (hereinafter, sometimes, referred to as compound (I)),has a clinically favorable pharmaceutical effect including CCRantagonist activity, especially excellent CCR5 antagonist activity, andcompleted the present invention.

Thus, the present invention provides:

[1] A compound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted;

R³ is a hydrogen atom, a lower alkyl group which may be substituted or alower alkoxy group which may be substituted;

Z¹ is a 5- or 6-membered aromatic ring which may be further substituted;

Z² is a group represented by -Z^(2a)-W¹-Z^(2b)- wherein Z^(2a) andZ^(2b) are each O, S(O)_(m) (wherein m is 0, 1 or 2), an imino groupwhich may be substituted, or a bond; and W¹ is an alkylene chain whichmay be substituted, an alkenylene chain which may be substituted, or abond;

n is an integer of 0 to 4;

Y is O, S(O)_(p) (wherein p is 0, 1 or 2), CH₂ or NR⁴ (wherein R⁴ is ahydrogen atom, a hydrocarbon group which may be substituted, aheterocyclic group which may be substituted, or an acyl group which maybe substituted); and

R² is (1) an amino group which may be substituted, in which the nitrogenatom may be converted to a quaternary ammonium or an oxide, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide, (3) a group represented by the formula:

wherein k is 0 or 1; when k is 0, the phosphorus atom may form aphosphonium salt; R⁵ and R⁶ are each a hydrocarbon group which may besubstituted, a hydroxy group which may be substituted or an amino groupwhich may be substituted; or R⁵ and R⁶ may be bonded to each other toform a ring with the adjacent phosphorus atom, (4) an amidino groupwhich may be substituted, or (5) a guanidino group which may besubstituted, or a salt thereof;

[2] A prodrug of the compound according to the above [I];

[3] The compound according to the above [1], wherein R¹ is a benzene, afuran, a thiophene, a pyridine, a cyclopentane, a cyclohexane, apyrrolidine, a piperidine, a piperazine, a morpholine, a thiomorpholineor a tetrahydropyran, each of which may be substituted;

[4] The compound according to the above [1], wherein R¹ is a benzenewhich may be substituted;

[5] The compound according to the above [1], wherein n is 2;

[6] The compound according to the above [1], wherein Z¹ is a benzenewhich may be substituted with a substituent selected from (1) a halogenatom, (2) a C₁₋₄ alkyl group which may be substituted with a halogenatom, and (3) a C₁₋₄ alkoxy group which may be substituted with ahalogen atom;

[7] The compound according to the above [1], wherein Z¹ is a benzenewhich may be substituted with a methyl group or a trifluoromethyl group;

[8] The compound according to the above [1], wherein Z² is a grouprepresented by -Z^(2a)-W²-Z^(2b)- wherein Z^(2a) and Z^(2b) are each O,S(O)_(m) (wherein m is 0, 1 or 2), an imino group which may besubstituted, or a bond; and W² is an alkylene chain which may besubstituted;

[9] The compound according to the above [1], wherein Z² is —CH₂—,—CH(OH)—, or —S(O)_(m)—CH₂— (wherein m is 0, 1 or 2);

[10] The compound according to the above [1], wherein Z² is a grouprepresented by —S(O)_(m)—CH₂— (wherein m is 0, 1 or 2);

[11] The compound according to the above [1], wherein R² is (1) an aminogroup which may be substituted, in which the nitrogen atom may beconverted to a quaternary ammonium or an oxide, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide, (3) an amidino group which may be substituted, or (4) a guanidinogroup which may be substituted;

[12] The compound according to the above [1], wherein R² is an aminogroup which may be substituted, or a nitrogen-containing heterocyclicgroup which may be substituted and may contain a sulfur atom or anoxygen atom as a ring-constituting atom;

[13] The compound according to the above [1], wherein R² is representedby the formula —NRR′ (wherein R and R′ are each an aliphatic hydrocarbongroup which may be substituted, or an alicyclic heterocyclic group whichmay be substituted);

[14] The compound according to the above [1], wherein R² is anitrogen-containing aromatic heterocyclic group which may besubstituted;

[15] The compound according to the above [1], wherein R² is animidazolyl group which may be substituted or a triazolyl group which maybe substituted;

[16] The compound according to the above [1], wherein R¹ is a benzene, afuran, a thiophene, a pyridine, a cyclopentane, a cyclohexane, apyrrolidine, a piperidine, a piperazine, a morpholine, a thiomorpholineor a tetrahydropyran, each of which may be substituted with a halogen, anitro, a cyano, a C₁₋₆ alkyl, a C₁₋₆ alkoxy, a C₁₋₆ alkoxy-C₁₋₆ alkyl ora C₁₋₆ alkoxy-C₁₋₆ alkoxy,

a Y-containing ring is a 7- to 10-membered ring which may contain anoxygen atom, a nitrogen atom or a sulfur atom which may be oxidized, asa ring-constituting atom, and may have, as a substituent, an alkyl whichmay be substituted, an alkenyl which may be substituted, an aryl whichmay be substituted, a heterocyclic group which may be substituted orformyl,

Z¹ is a benzene which may be substituted with substituent(s) selectedfrom (1) a halogen atom, (2) a C₁₋₄ alkyl group which may be substitutedwith halogen atom(s) and (3) a C₁₋₄ alkoxy group which may besubstituted with halogen atom(s),

Z² is -Z^(2a)-W¹-Z^(2b)- wherein Z^(2a) and Z^(2b) are each I, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted with aC₁₋₄ alkyl group or a bond, and W¹ is a bond, or a C₁₋₄ alkylene chainor a C₂₋₄ alkenylene chain, each of which may have, as a substituent, aC₁₋₆ alkyl, a hydroxy group, a hydroxyimino or a C₁₋₆ alkoxyimino, and

R² is an amino group which may be substituted with a C₁₋₄ alkyl group,or a nitrogen-containing heterocyclic group which may contain a sulfuratom or an oxygen atom as a ring-constituting atom and may besubstituted with a C₁₋₄ alkyl group;

[17] A compound represented by the formula:

wherein R^(1a) is a (C₁₋₆ alkoxy-C₁₋₆ alkoxy)phenyl;

R^(2a) is (1) an N—C₁₋₆ alkyl-N-tetrahydropyranylamino, (2) animidazolyl which may be substituted with a C₁₋₆ alkyl which may besubstituted, or (3) a triazolyl which may be substituted with a C₁₋₆alkyl which may be substituted;

R³ is a hydrogen atom, a lower alkyl group which may be substituted or alower alkoxy group which may be substituted;

Y^(a) is (1) an oxygen atom, (2) S(O)_(p) (wherein p is 0, 1 or 2), (3)CH₂ or (4) an imino group which may have, as a substituent, a formyl, aC₁₋₆ alkyl which may be substituted, a C₂₋₆ alkenyl which may besubstituted, an aryl which may be substituted, a heterocyclic groupwhich may be substituted, an arylmethyl which may be substituted or aheterocyclic methyl which may be substituted;

N′ is 1, 2 or 3;

na is 0 or 1;

Z^(2a) is a bond, S, SO or SO₂; and

the other symbols have the same meanings as defined above, or a saltthereof;

[18] The compound according to the above [17], wherein Z^(2a) is SO;

[19] The compound according to the above [18], wherein Z^(2a) is SOhaving a configuration of (S);

[20] The compound according to the above [17], wherein Y^(a) is an iminogroup which may have, as a substituent, a formyl, a C₁₋₆ alkyl which maybe substituted, a C₁₋₆ alkenyl which may be substituted, an aryl whichmay be substituted, a heterocyclic group which may be substituted, anarylmethyl which may be substituted or a heterocyclic methyl which maybe substituted;

[21](S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

[22](S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

[23] A process for producing a compound represented by the formula:

wherein R^(2″) is (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom, inwhich the nitrogen atom may be converted to a quaternary ammonium, or(3) a group represented by the formula (a); and the other symbols havethe same meanings as defined above, or a salt thereof, which comprisessubjecting a compound represented by the formula:

wherein each symbol has the same meaning as defined above, or a saltthereof or a reactive derivative thereof, and a compound represented bythe formula:

wherein each symbol has the same meaning as defined above, or saltthereof, to a condensation reaction, and then optionally to adeprotection reaction, an oxidation/reduction reaction and/or aquaternization reaction;

[24] A pharmaceutical composition comprising a compound represented bythe formula (I), a salt thereof or a prodrug thereof;

[25] The pharmaceutical composition according to the above [24], whichis a CCR antagonist;

[26] The pharmaceutical composition according to the above [25], whereinCCR is CCR5 and/or CCR2;

[27] The pharmaceutical composition according to the above [25], whereinCCR is CCR5;

[28] The pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for HIV infection, chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, nephritis/nephropathy orarteriosclerosis;

[29] The pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for HIV infection;

[30] The pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for AIDS;

[31] The pharmaceutical composition according to the above [24], whichis a suppressive agent for disease progression of AIDS;

[32] A process for preventing or treating HIV infection, chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, nephritis/nephropathy,arteriosclerosis or graft-versus-host diseases, which comprisesadministering an effective amount of the compound according to the above[I], a salt thereof or a prodrug thereof, to a subject in need thereof;and

[33] Use of the compound according to the above [I], a salt thereof or aprodrug thereof, for manufacturing a prophylactic and/or therapeuticagent for HIV infection, chronic rheumatoid arthritis, autoimmunediseases, allergic diseases, ischemic brain cell disorder, cardiacinfarction, nephritis/nephropathy, arteriosclerosis or graft-versus-hostdiseases.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above-described formula (I), the “5- or 6-membered ring” in the“5- or 6-membered ring group which may be substituted” represented by R¹may be exemplified by a group which is formed by eliminating onehydrogen atom from 6-membered aromatic hydrocarbon such as benzene,etc.; 5- or 6-membered aliphatic hydrocarbon such as cyclopentane,cyclohexane, cyclopentene, cyclohexene, cyclopentanediene,cyclohexanediene, etc.; a 5- or 6-membered aromatic heterocyclic ringcontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom, such as furan,thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole,isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine,triazole, etc.; a 5- or 6-membered non-aromatic heterocyclic ringcontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom, such astetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane,pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine,thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran,tetrahydrothiopyran, etc.; and the like. Among them, the “5- or6-membered ring” is preferably benzene, furan, thiophene, pyridine,cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine,morpholine, thiomorpholine, tetrahydropyran (preferably a 6-memberedring), and the like, it being particularly preferably benzene.

The “substituent” which may be carried by the “5- or 6-membered ring” ofthe “5- or 6-membered ring group which may be substituted” representedby R¹ may be exemplified by halogen atom, nitro, cyano, alkyl which maybe substituted, cycloalkyl which may be substituted, hydroxy group whichmay be substituted, thiol group which may be substituted (wherein thesulfur atom may be oxidized, or may form sulfinyl which may besubstituted or sulfonyl which may be substituted), amino group which maybe substituted, acyl which may be substituted, carboxyl group which maybe esterified, an aromatic group which may be substituted, and the like.

Examples of the “halogen” as the substituent of R¹ include fluorine,chlorine, bromine, iodine and the like, it being particularly preferablyfluorine and chlorine.

The “alkyl” of the “alkyl which may be substituted” as the substituentof R¹ may be exemplified by linear or branched alkyl having 1 to 10carbon atoms, for example, C₁₋₁₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferablylower (C₁₋₆) alkyl. Examples of the substituent of the “alkyl which maybe substituted” include halogen (for example, fluorine, chlorine,bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group whichmay be substituted (for example, thiol, C₁₋₄ alkylthio, etc.), aminogroup which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy whichmay halogenated (for example, methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), andthe like, and the number of the substituents is preferably 1 to 3.

Examples of the cycloalkyl of the “cycloalkyl which may be substituted”as the substituent of R¹ include C₃₋₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Examples of the“substituent” in the “cycloalkyl which may be substituted” includehalogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, thiol group which may be substituted (for example,thiol, C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., andthe like), carboxyl group which may be esterified or amidated (forexample, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy whichmay be halogenated (for example, methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), andthe like, and the number of the substituents is preferably 1 to 3.

The substituent of the “hydroxy group which may be substituted” as thesubstituent of R¹ may be exemplified by (1) alkyl which may besubstituted (for example, C₁₋₁₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower(C₁₋₆) alkyl; and the like);

(2) cycloalkyl which may be substituted and may contain heteroatom(s)(for example, C₃₋₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.; 5- or 6-membered saturatedheterocyclic group containing 1 or 2 heteroatoms, such astetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl,piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrothiopyranyl, etc., and preferably tetrahydropyranyl, etc.; andthe like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl; and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.; and the like);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkylsuch as benzyl, phenethyl, etc.; and the like);

(6) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms, such as acetyl, propionyl, butyryl,isobutyryl, etc., alkylsulfonyl having 1 to 4 carbon atoms (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

The substituent which may be carried by the above-described (1) alkylwhich may be substituted, (2) cycloalkyl which may be substituted, (3)alkenyl which may be substituted, (4) cycloalkenyl which may besubstituted, (5) aralkyl which may be substituted, (6) acyl which may besubstituted, and (7) aryl which may be substituted, may be exemplifiedby halogen (for example, fluorine, chlorine, bromine, iodine, etc.),nitro, cyano, hydroxy group, thiol group which may be substituted (forexample, thiol, C₁₋₄ alkylthio, etc.), amino group which may besubstituted (for example, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole,etc., and the like), carboxyl group which may be esterified or amidated(for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkyl which may behalogenated (for example, trifluoromethyl, methyl, ethyl, etc.), C₁₋₆alkoxy which may be halogenated (for example, methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably C₁₋₄ alkoxywhich may be halogenated), formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), a 5- or 6-membered aromatic heterocyclic ringwhich may be substituted [for example, a 5- or 6-membered aromaticheterocyclic ring containing 1 to 4 heteroatoms of one or two kindsselected from a nitrogen atom, a sulfur atom and an oxygen atom, such asfuran, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole,isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazole, etc.; examples of the substituent which may becarried by the heterocyclic ring include halogen (for example, fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiolgroup, amino group, carboxyl group, C₁₋₄ alkyl which may be halogenated(for example, trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy whichmay be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like; and the number ofthe substituents is preferably 1 to 3], and the like; and the number ofthe substituents is preferably 1 to 3.

The substituent of the “thiol group which may be substituted” as thesubstituent of R¹ may be exemplified by the same one as the “substituentof hydroxy group which may be substituted as the substituent of R¹,” andpreferred among them are:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl; and the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc.);

(3) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkylsuch as benzyl, phenethyl, etc.);

(4) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

The substituent which may be carried by the above-described (1) alkylwhich may be substituted, (2) cycloalkyl which may be substituted, (3)aralkyl which may be substituted and (4) aryl which may be substitutedmay be exemplified by halogen (for example, fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, hydroxy group, thiol group which may besubstituted (for example, thiol, C₁₋₄ alkylthio, etc.), amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy whichmay be halogenated (for example, methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), andthe like, and the number of the substituents is preferably 1 to 3.

The substituent of the “amino group which may be substituted” as thesubstituent of R¹ may be exemplified by the same one as the “substituentof hydroxy group which may be substituted as the substituent of R¹,” andthe number of substituents on the amino group may be 1 or 2. Among them,the substituent is preferably:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, and the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc., and the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.; and the like);

(5) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.) and the like);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) acyl which may be substituted, and (6)aryl which may be substituted, include halogen (for example, fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiolgroup which may be substituted (for example, thiol, C₁₋₄ alkylthio,etc.), amino group which may be substituted (for example, amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.), carboxyl group which may beesterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄alkoxy which may be halogenated (for example, methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄alkoxy which may be halogenated (for example, methoxymethoxy,methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,trifluoroethoxyethoxy, etc.), formyl, C₂₋₄ alkanoyl (for example,acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number ofthe substituents is preferably 1 to 3.

Further, the substituents of the “amino which may be substituted” as thesubstituent of R¹ may be bonded to each other to form a cyclic aminogroup (for example, a group which is formed by eliminating one hydrogenatom from the ring-constituting nitrogen atom of a 5- or 6-membered ringsuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc. so that a bond is madeavailable on the nitrogen atom, and the like). This cyclic amino groupmay be substituted, and examples of the substituent include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.),carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl), and the like, while thenumber of the substituents is preferably 1 to 3.

The “acyl which may be substituted” as the substituent of R¹ may beexemplified by a group in which

(1) hydrogen;

(2) alkyl which may be substituted (for example, C-₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl and the like);

(3) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., and the like);

(4) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl and the like);

(5) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., and the like);

(6) 5- or 6-membered monocyclic aromatic group which may be substituted(for example, phenyl, pyridyl, etc.) or the like is bonded to a carbonylgroup or a sulfonyl group (for example, formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl,ethanesulfonyl, etc.). Examples of the substituent which may be carriedby the above-described (2) alkyl which may be substituted, (3)cycloalkyl which may be substituted, (4) alkenyl which may besubstituted, (5) cycloalkenyl which may be substituted, and (6) 5- or6-membered monocyclic aromatic group which may be substituted, includehalogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, thiol group which may be substituted (for example,thiol, C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.),carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkyl-carbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated(for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.); C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

The “carboxyl which may be esterified” as the substituent of R¹ may beexemplified by a group in which

(1) hydrogen;

(2) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl and the like);

(3) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., and the like);

(4) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl and the like);

(5) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., and the like);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.)or the like is bonded to a carbonyloxy group, and preferably carboxyl,lower (C₁₋₆) alkoxycarbonyl, aryloxycarbonyl (for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl,naphthoxycarbonyl, etc.), and the like. Examples of the substituentwhich may be carried by the above-described (2) alkyl which may besubstituted, (3) cycloalkyl which may be substituted, (4) alkenyl whichmay be substituted, (5) cycloalkenyl which may be substituted, and (6)aryl which may be substituted, include halogen (for example, fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiolgroup which may be substituted (for example, thiol, C₁₋₄ alkylthio,etc.), amino group which may be substituted (for example, amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., and the like), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

The “aromatic group” of the “aromatic group which may be substituted” asthe substituent of R¹ may be exemplified by a 5- or 6-memberedhomocyclic or heterocyclic aromatic group such as phenyl, pyridyl,furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazolyl, etc.; a fused heterocyclic aromatic group suchas benzofuran, indole, benzothiophene, benzoxazole, benzothiazole,indazole, benzimidazole, quinoline, isoquinoline, quinoxaline,phthalazine, quinazoline, cinnoline, imidazopyridine, etc.; and thelike. Examples of the substituent of these aromatic groups includehalogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, thiol group which may be substituted (for example,thiol, C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., andthe like), carboxyl group which may be esterified or amidated (forexample, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.); C₁₋₄ alkyl which may behalogenated (for example, trifluoromethyl, methyl, ethyl, etc.); C₁₋₄alkoxy which may be halogenated (for example, methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl(for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number ofthe substituents is preferably 1 to 3.

The number of the above substituents of R¹ may be 1 to 4, preferably 1to 2, and the substituents which may be identical or different from eachother may be present at any positions of the ring. When the “5- or6-membered ring” of the “5- to 6-membered ring which may be substituted”represented by R¹ has two or more substituents, two of the substituentsmay be bonded to each other to form, for example, lower (C₁₋₆) alkylene(for example, trimethylene, tetramethylene, etc.), lower (C₁₋₆)alkyleneoxy (for example, —CH₂—O—CH₂—, —O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—,—O—CH₂—CH₂—CH₂—CH₂—, —O—C (CH₃)(CH₃)—CH₂—CH₂—, etc.), lower (C₁₋₆)alkylenethio (for example, —CH₂—S—CH₂—, —S—CH₂—CH₂—, —S—CH₂—CH₂—CH₂—,—S—CH₂—CH₂—CH₂—CH₂—, —S—C(CH₃)(CH₃)—CH₂—CH₂—, etc.), lower (C₁₋₆)alkylenedioxy (for example, —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—,etc.), lower (C₁₋₆) alkylenedithio (for example, —S—CH₂—S—,—S—CH₂—CH₂—S—, —S—CH₂—CH₂—CH₂—S—, etc.), oxy-lower (C₁₋₆) alkyleneamino(for example, —O—CH₂—NH—, —O—CH₂—CH₂—NH—, etc.), oxy-lower (C₁₋₆)alkylenethio (for example, —O—CH₂—S—, —O—CH₂—CH₂—S—, etc.), lower (C₁₋₆)alkyleneamino (for example, —NH—CH₂—CH₂—, —NH—CH₂—CH₂—CH₂—, etc.), lower(C₁₋₆) alkylenediamino (for example, —NH—CH₂—NH—, —NH—CH₂—CH₂—NH—,etc.), thialower (C₁₋₆) alkyleneamino (for example, —S—CH₂—NH—,—S—CH₂—CH₂—NH—, etc.), lower (C₂₋₆) alkenylene (for example,—CH₂—CH═CH—, —CH₂—CH₂—CH═CH—, —CH₂—CH═CH—CH₂—, etc.) lower (C₄₋₆)alkadienylene (for example, —CH═CH—CH═CH—, etc.), and the like.

Further, the divalent group formed by bonding of two substituents of R¹may contain 1 to 3 substituents which are the same as the “substituents”which may be carried by the “5- or 6-membered ring” of the “5- or6-membered ring which may be substituted” represented by R¹ (halogenatom, nitro, cyano, alkyl which may be substituted, cycloalkyl which maybe substituted, hydroxy group which may be substituted, thiol groupwhich may be substituted (wherein the sulfur atom may be oxidized, ormay form sulfinyl group which may be substituted or sulfonyl group whichmay be substituted), amino group which may be substituted, acyl whichmay be substituted, carboxyl group which may be esterified or amidated,an aromatic group which may be substituted, and the like).

The “substituent” which may be carried by the “5- or 6-membered ring” ofthe “5- or 6-membered ring group which may be substituted” representedby R¹ may be exemplified by, in particular, lower (C₁₋₄) alkyl which maybe halogenated or lower (C₁₋₄) alkoxylated (for example, methyl, ethyl,t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl,butoxymethyl, methoxyethyl, ethoxylethyl, propoxyethyl, butoxyethyl,etc.), lower (C₁₋₄) alkoxy which may be halogenated or lower (C₁₋₄)alkoxylated (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxy,trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy,butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy,methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.),halogen (for example, fluorine, chlorine, etc.), nitro, cyano, aminowhich may be substituted with one or two of lower (C₁₋₄) alkyl, formylor lower (C₂₋₄) alkanoyl (for example, amino, methylamino,dimethylamino, formylamino, acetylamino, etc.), a 5- or 6-memberedcyclic amino group (for example, 1-pyrrolidinyl, 1-piperazinyl,1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl,4-tetrahydropyranyl, etc.), and the like.

Examples of the lower alkyl group of the “lower alkyl group which may besubstituted” represented by R³ above include C₁₋₆ alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, etc., and the like.

Examples of the lower alkoxy group of the “lower alkoxy group which maybe substituted” represented by R³ above include C₁₋₆ alkoxy such asmethoxy, ethoxy, propoxy, butoxy, etc., and the like.

Examples of the substituent which may be carried by the “lower alkylgroup which may be substituted” and “lower alkoxy group which may besubstituted” include halogen (for example, fluorine, chlorine, bromine,iodine), hydroxy group, amino, mono(lower alkyl)amino, di(loweralkyl)amino, lower alkanoyl and the like.

The lower alkyl carried by the mono(lower alkyl)amino and di(loweralkyl)amino may be exemplified by the same lower alkyl group of the“lower alkyl group which may be substituted” represented by R³ above.

The lower alkanoyl may be exemplified by C₂₋₆ alkanoyl such as acetyl,propionyl, butyryl, isobutyryl, etc.

Among them, as for R³, the lower C₁₋₆ alkyl group which may besubstituted is preferred, and particularly a methyl group which may besubstituted is preferred.

With respect to a group of the above-described NR⁴ represented by Y, the“hydrocarbon group” of the “hydrocarbon group which may be substituted”represented by R⁴ may be exemplified by:

(1) alkyl (for example, C₁₋₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower(C₁₋₆) alkyl, more preferably lower (C₁₋₄) alkyl and the like);

(2) cycloalkyl (for example, C₃₋₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and the like);

(3) alkenyl (for example, alkenyl having 2 to 10 carbon atoms, such asallyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C₂₋₆)alkenyl and the like);

(4) cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms,such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc., and the like);

(5) alkynyl (for example, alkynyl having 2 to 10 carbon atoms, such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc.,preferably lower (C₂₋₆) alkynyl and the like);

(6) aralkyl (for example, phenyl-C₁₋₄ alkyl (for example, benzyl,phenethyl, etc.) and the like);

(7) aryl (for example, phenyl, naphthyl, etc.);

(8) cycloalkyl-alkyl (for example, C₃₋₇ cycloalkyl-C₁₋₄ alkyl such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, etc.); and the like.

Examples of the substituent which may be carried by the above-described(1) alkyl, (2) cycloalkyl, (3) alkenyl, (4) cycloalkenyl, (5) alkynyl,(6) aralkyl, (7) aryl and (8) cycloalkyl-alkyl, include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.),carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (forexample, trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy (forexample, —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), sulfonamide which may besubstituted [for example, a group formed by bonding of amino group whichmay be substituted (for example, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole,etc.) with —SO₂—, etc.], formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), a heterocyclic group which may be substituted,and the like, and the number of the substituents is preferably 1 to 3.

The “heterocyclic group” of the “heterocyclic group which may besubstituted” and the “heterocyclic group which may be substituted”represented by R⁴, may be exemplified by a group formed by eliminatingone hydrogen atom from an aromatic heterocyclic ring or a non-aromaticheterocyclic ring, and the like. Examples of such aromatic heterocyclicring include a 5- or 6-membered aromatic heterocyclic ring containing 1to 4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom, such as furan, thiophene, pyrrole,imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole,oxadiazole, thiadiazole or the like, while examples of such non-aromaticheterocyclic ring include a 5- or 6-membered non-aromatic heterocyclicring containing 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom, such astetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane,oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, etc., a non-aromatic heterocyclic ring in which all orpart of the bonds in the above-mentioned aromatic heterocyclic ring aresaturated bonds (preferably, an aromatic heterocyclic ring such aspyrazole, thiazole, oxazole, tetrazole, etc.), and the like.

The substituent of the “heterocyclic group” of the “heterocyclic groupwhich may be substituted” represented by R⁴, may be exemplified by thesame substituent of the “hydrocarbon group” of the “hydrocarbon groupwhich may be substituted” represented by R⁴.

The hydrocarbon group which may be substituted is preferably C₁₋₆ alkylwhich may be halogenated or hydroxylated and C₂₋₆ alkenyl which may behalogenated or hydroxylated.

The “acyl group which may be substituted” represented by R⁴ may beexemplified by the same one as the “acyl group which may be substituted”as the substituent which may be carried by the “5- or 6-membered ring”of the “5- or 6-membered ring which may be substituted” represented byR¹, and among these, C₁₋₄ alkylsulfonyl which may be halogenated orhydroxylated, formyl, C₂₋₅ alkanoyl which may be halogenated orhydroxylated, and the like are more preferred.

As for R⁴, C₁₋₄ alkyl which may be halogenated or hydroxylated, formyl,C₂₋₅ alkanoyl which may be halogenated or hydroxylated, and the like aremore preferred, and propyl, isobutyl, isobutenyl or3-hydroxy-2-methylpropyl are particularly preferred. Another preferredembodiment of R⁴ may be exemplified by a group represented by theformula —(CH₂)_(s)—R^(x) wherein s is 0 or 1 and R^(x) is a 5- or6-membered ring which may be substituted (for example, the same one asthe “5- or 6-membered ring which may be substituted” represented by R¹,etc.; preferably phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl,tetrazolyl, etc., each of which may be substituted with halogen, C₁₋₄alkyl which may be halogenated or hydroxylated, C₁₋₄ alkoxy which may behalogenated or hydroxylated, etc.), and the like.

Among these, R⁴ is preferably 1) C₁₋₆ alkyl, 2) C₂₋₆ alkenyl, 3) C₆₋₁₀aryl, 4) C₆₋₁₀ arylmethyl, 5) heterocyclic group and 6) heterocyclicmethyl (wherein the above 1) and 2) may be substituted with halogen orhydroxy group; and the above 3), 4), 5) and 6) may be substituted withhalogen, C₁₋₆ alkyl which may be substituted with halogen or hydroxygroup, or C₁₋₆ alkoxy which may be substituted with halogen or hydroxygroup).

n is preferably 1 or 2, and particularly preferably 2.

In formula (I) above, the “5- or 6-membered aromatic ring which may besubstituted” represented by Z¹ may be exemplified by a 6-memberedaromatic hydrocarbon such as benzene; a 5- to 6-membered aromaticheterocyclic ring containing 1 to 4 heteroatoms of one or two kindsselected from a nitrogen atom, a sulfur atom and an oxygen atom, such asfuran, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole,isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazole, etc.; a fused aromatic heterocyclic ring such asbenzofuran, indole, benzothiophene, benzoxazole, benzothiazole,indazole, benzimidazole, quinoline, isoquinoline, quinoxaline,phthalazine, quinazoline, cinnoline, imidazopyridine, etc.; and thelike. Among them, preferred are benzene, furan, thiophene, pyridine,pyridazine, pyrimidine, benzimidazole and the like, and particularlypreferably used are benzene, pyridine, pyridazine and benzimidazole(preferably benzene).

The “5- or 6-membered aromatic ring which may be substituted”represented by Z¹ may have the same substituent as the “substituent”which may be carried by the “5- or 6-membered ring” of the “5- or6-membered ring which may be substituted” represented by R¹, and amongthe substituents, a halogen atom (for example, fluorine, chlorine,bromine, etc.), a C₁₋₄ alkyl group which may be substituted with halogenatom(s) (for example, methyl, ethyl, trifiluoromethyl, trifluoroethyl,etc.), a C₁₋₄ alkoxy group which may be substituted with halogen atom(s)(for example, methoxy, ethoxy, propoxy, trifluoromethoxy,trifluoroethoxy, etc.) and the like are preferred. However, it ispreferred that there is no other substituent than X² and Z², and it ispreferred that when Z¹ is a 6-membered ring (preferably benzene), thesite of substitution of Z² is para to X². Further, as for thesubstituent of Z¹, benzene which may be substituted with 1) a halogenatom, 2) a C₁₋₄ alkyl group which may be substituted with halogenatom(s) or 3) C₁₋₄ alkoxy group which may be substituted with halogenatom(s) is preferred, and in particular, benzene which may besubstituted with a methyl group or a trifluoromethyl group is preferred.

In formula (I) above, with respect to the formulas -Z^(2a)-W¹-Z^(2b)-and -Z^(2a)-W²-Z^(2b)- represented by Z², the substituent (R^(a)) of the“imino group which may be substituted” represented by each of Z^(2a) andZ^(2b) may be exemplified by hydrogen atom, lower (C₁₋₆) alkyl which maybe substituted [for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,hydroxy-C₁₋₆ alkyl (for example, hydroxyethyl, hydroxypropyl,hydroxybutyl, etc.), halogenated C₁₋₆ alkyl (for example,trifluoromethyl, trifluoroethyl, etc.), cyanated C₁₋₆ alkyl (forexample, cyanoethyl, cyanopropyl, etc.), carboxyl-C₁₋₆ alkyl which maybe esterified or amidated, etc.], formyl, lower (C₂₋₅) alkanoyl (forexample, acetyl, propionyl, butyryl, etc.), lower (C₁₋₅) alkylsulfonyl(methylsulfonyl, ethylsulfonyl, etc.), and the like.

The alkylene chain of the “alkylene group which may be substituted”represented by W¹ and W² may be exemplified by the alkylene chainrepresented by —(CH₂)_(k1)— (wherein k1 is an integer of 1 to 4) or thelike. The alkenylene group of the “alkenylene group which may besubstituted” represented by W¹ may be exemplified by the alkenylenechain represented by —(CH₂)_(k2)—(CH═CH)—(CH₂)_(k3)— (wherein k2 and k3are identical or different, and represent 0, 1 or 2, respectively,provided that the sum of k2 and k3 is 2 or less) and the like.

The alkylene group and alkenylene group represented by the W¹ and W² maybe substituted at any arbitrary position (preferably on a carbon atom),and such substituent may be any substituent capable of bonding to thealkylene chain or alkenylene chain which constitutes the straight chainmoiety. Examples thereof include lower (C₁₋₆) alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C₃₋₇)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc.), formyl, lower (C₂₋₇) alkanoyl, (forexample, acetyl, propionyl, butyryl, etc.), phosphono which may beesterified, carboxyl group which may be esterified or amidated, hydroxygroup, oxo, hydroxyimino group, lower (C₁₋₆) alkoxyimino group which maybe substituted and the like, and preferably lower alkyl having 1 to 6carbon atoms (preferably, C₁₋₃ alkyl), hydroxy group, oxo, hydroxyiminogroup, lower (C₁₋₆) alkoxyimino group (which may be substituted with apolar group such as hydroxy group, cyano group, carboxyl group which maybe esterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.),etc.) and the like.

The phosphono group which may be esterified may be exemplified by agroup represented by P(O)(OR⁷)(OR⁸) wherein R⁷ and R⁸ are each hydrogen,an alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having3 to 7 carbon atoms, or R⁷ and R⁸ may be bonded to each other to form a5- to 7-membered ring.

In the above-described formula, the alkyl group having 1 to 6 carbonatoms represented by R⁷ and R⁸ may be exemplified by methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl and the like, and the cycloalkyl grouphaving 3 to 7 carbon atoms may be exemplified by cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferredis a chained lower alkyl having 1 to 6 carbon atoms, and more preferredis lower alkyl having 1 to 3 carbon atoms. R⁷ and R⁸ may be identical ordifferent from each other, preferably identical. Further, when R⁷ and R⁸are bonded to each other to form a 5- to 7-membered ring, R⁹ and R¹⁰ arebonded to each other to form a linear C₂₋₄ alkylene side chainrepresented by —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₄—. This side chain may besubstituted, and examples of such substituent include hydroxy group,halogen and the like.

The ester derivative of the above-described carboxyl group which may beesterified may be exemplified by a derivative in which a carboxyl groupis bonded to an alkyl group having 1 to 6 carbon atoms or a cycloalkylgroup having 3 to 7 carbon atoms, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl and the like.

The amide derivative of the above-described carboxyl group which may beamidated may be exemplified by a derivative in which a carboxyl group isbonded to an alkylamino group having 1 to 6 carbon atoms, acycloalkylamino group having 3 to 7 carbon atoms or 5- to 8-memberedcyclic amine (for example, pyrrolidine, piperidine, morpholine, etc.),for example, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl,pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl and the like.

For Z², preferably, one of Z^(2a) and Z^(2b) is O, S(O)_(m) (wherein mis 0, 1 or 2), or —N(R^(a))— (wherein R^(a) is a hydrogen atom or alower C₁₋₄ alkyl group which may be substituted), the other being abond, and W is —(CH₂)_(p)— (wherein p is an integer of 1 to 3), or Z² isa divalent group of the formula —CH(OH)—. More preferably, one of Z^(2a)and Z^(2b) is O or S(O)_(m) (wherein m is 0, 1 or 2), the other being abond, and W is —(CH₂)_(p)— (wherein p is an integer of 1 to 3), or Z² isa divalent group of the formula —CH(OH)—. Even more preferably, Z² is—CH₂—, —CH(OH)—, —S(O)_(m)—CH₂— (wherein m is 0, 1 or 2), with—S(O)_(m)—CH₂— (wherein m is 0, 1 or 2) being particularly preferred. Inparticular, when Z^(2a) is bonded to Z¹, Z² is preferably —SOCH₂—.

Z^(2a) represents a bond, S, SO or SO₂, and among them, SO is preferred.In this case, the configuration of SO is preferably (S).

The bonding position of Z² with respect to Z¹ is such that when Z¹ is abenzene ring for example, any position may be selected, but the paraposition is preferred.

In the above formula (I), the “amino group which may be substituted, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide” represented by R² may be exemplified by an amino group which mayhave 1 or 2 substituents, an amino group which has three substituents,in which the nitrogen atom is converted to quaternary ammonium, and thelike. When the amino group has two or more substituents on its nitrogenatom, the substituents may be identical or different; and when thenitrogen atom has 3 substituents, the amino group may be of any typeamong the following formulas, —N⁺R^(p)R^(p)R^(p), —N⁺R^(p)R^(p)R^(q),and —N+R^(p)R^(q)R^(r), wherein R^(p), R^(q), and R^(r) are differentfrom each other, each being hydrogen or a substituent. Examples of thecounter anion of the amino group, in which the nitrogen atom isconverted to quaternary ammonium include, in addition to anions ofhalogen (for example, Cl⁻, Br⁻, I⁻, etc.), anions derived from inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; anions derived from organic acids such asformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; and anions derived from acidic amino acids such as asparticacid, glutamic acid, etc., and among them, Cl¹, Br⁻, I⁻ and the like arepreferred.

Examples of the substituent of the amino group include:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, and the like); and

(2) cycloalkyl which may be substituted (for example, C₃₋₈ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyanooctyl, etc., and the like);

(2-1) the cycloalkyl may contain one heteroatom selected from a sulfuratom, an oxygen atom and a nitrogen atom, forming oxirane, thiolane,aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide,piperidine, etc. (preferably, a 6-membered ring such as tetrahydropyran,tetrahydrothiopyran, piperidine, etc.), and the bond with the aminogroup may be preferably present at the 3- or 4-position (preferably atthe 4-position);

(2-2) also, the cycloalkyl may be fused to a benzene ring, formingindane (for example, indan-1-yl, indan-2-yl, etc.),tetrahydronaphthalene (for example, tetrahydronaphthalen-5-yl,tetrahydronaphthalen-6-yl, etc.), or the like (preferably, indane,etc.);

(2-3) further, the cycloalkyl may be bridged via a straight atomic chainhaving 1 or 2 carbon atoms, forming a bridged cyclic hydrocarbon residuesuch as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl, etc. (preferably, cyclohexyl bridged via a straightatomic chain having 1 to 2 carbon atoms, and more preferably,bicyclo[2.2.1]heptyl, etc.);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl, and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cylcohexenylmethyl, etc.);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.), and the like);

(6) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.), alkoxycarbonyl having 1to 4 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, etc.), aralkyloxycarbonyl having 7 to 10 carbonatoms (for example, benzyloxycarbonyl, etc.), and the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);

(8) a heterocyclic group which may be substituted (for example, a groupformed by eliminating one hydrogen atom from a 5- or 6-membered aromaticheterocyclic ring containing 1 to 4 heteroatoms of one or two kindsselected from a nitrogen atom, a sulfur atom and an oxygen atom, such asfuran, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole,isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazole, oxadiazole, thiadiazole, etc., or from a fusedheterocyclic aromatic group such as benzofuran, indole, benzothiophene,benzoxazole, benzothiazole, indazole, benzimidazole, quinoline,isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline,imidazopyridine, etc.; a group formed by eliminating one hydrogen atomfrom a 5- or 6-membered non-aromatic heterocyclic ring containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom, such as tetrahydrofuran, tetrahydrothiophene,dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine,imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine,oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, etc.; and the like; preferably, a group formed byeliminating a hydrogen atom from the 5- or 6-membered non-aromaticheterocyclic ring and the like; more preferably, a group formed byeliminating one hydrogen atom from a 5- or 6-membered non-aromaticheterocyclic ring containing one heteroatom, such as tetrahydrofuran,piperidine, tetrahydropyran, tetrahydrothiopyran, etc.); and the like.The substituents on the amino group may be bonded to each other to form5- to 7-membered cyclic amino such as piperidine, piperazine,morpholine, thiomorpholine, etc.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) aralkyl which may be substituted, (6) acylwhich may be substituted, (7) aryl which may be substituted, and (8) aheterocyclic group which may be substituted, include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.); lower (C₁₋₄) alkylwhich may be halogenated; lower (C₁₋₄) alkyl which may be substitutedwith a polar group such as hydroxy group, a cyano group, a carboxylgroup which may be esterified or amidated, etc. (for example,hydroxy-C₁₋₄ alkyl, cyano-C₁₋₄ alkyl, carboxyl-C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄ alkyl, mono-C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, di-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, pyrrolidinocarbonyl-C₁₋₄ alkyl,piperidinocarbonyl-C₁₋₄ alkyl, morpholinocarbonyl-C₁₋₄ alkyl,thiomorpholinocarbonyl-C₁₋₄ alkyl, etc.); C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.); C₁₋₄ alkylenedioxy (forexample, —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.); formyl; C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.); C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.); phenyl-lower (C₁₋₄) alkyl; C₃₋₇cycloalkyl; cyano; nitro; hydroxy group; thiol group which may besubstituted (for example, thiol, C₁₋₄ alkylthio, etc.); amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., and the like); carboxyl group which may beesterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.);lower (C₁₋₄) alkoxy-carbonyl; lower (C₇₋₁₀) aralkyloxy-carbonyl; oxogroup (preferably, halogen, lower (C₁₋₄) alkyl which may be halogenated,lower (C₁₋₄) alkoxy which may be halogenated, phenyl-lower (C₁₋₄) alkyl,C₃₋₇ cycloalkyl, cyano, hydroxy group, etc); and the like. The number ofthe substituents is preferably 1 to 3.

In the above formula (I), the “amino group which may be substituted, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide” represented by R² is preferably an amino group which may have 1to 3 substituents selected from:

(1) linear or branched lower (C₁₋₆) alkyl which may be substituted withone to three of halogen, cyano, hydroxy group or C₃₋₇ cycloalkyl;

(2) C₅₋₈ cycloalkyl which may be substituted with one to three ofhalogen, lower (C₁₋₄) alkyl which may be halogenated, or phenyl-lower(C₁₋₄) alkyl, which may contain one heteroatom selected from a sulfuratom, an oxygen atom and a nitrogen atom, which may be fused to abenzene ring, and which may be bridged via a straight atomic chainhaving 1 or 2 carbon atoms (for example, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl,piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo[2,2,1]heptyl,etc., each of which may be substituted);

(3) phenyl-lower (C₁₋₄) alkyl which may have one to three of halogen,lower (C₁₋₄) alkyl which may be halogenated, or lower (C₁₋₄) alkoxywhich may be halogenated;

(4) phenyl which may have one to three of halogen, lower (C₁₋₄) alkylwhich may be halogenated, or lower (C₁₋₄) alkoxy which may behalogenated; and

(5) a 5- to 6-membered aromatic heterocyclic group which may have one tothree of halogen, lower (C₁₋₄) alkyl which may be halogenated, lower(C₁₋₄) alkoxy group which may be halogenated, lower (C₁₋₄) alkoxy-lower(C₁₋₄) alkoxy which may be halogenated, phenyl-lower (C₁₋₄) alkyl,cyano, or hydroxy group (for example, a group formed by eliminating onehydrogen atom from furan, thiophene, pyrrole, pyridine, etc.).

In the above formula (I), the “nitrogen-containing heterocyclic ring” ofthe “nitrogen-containing heterocyclic group which may be substituted andwhich may contain a sulfur atom or an oxygen atom as thering-constituting atom, in which the nitrogen atom may be converted to aquaternary ammonium or an oxide” represented by R², may be exemplifiedby a 5- to 6-membered aromatic heterocyclic ring containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom, such as pyrrole, imidazole, pyrazole, thiazole,oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, etc. or afused aromatic heterocyclic ring such as benzofuran, indole,benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole,quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, imidazopyridine, etc.; a 5- to 8-membered non-aromaticheterocyclic ring containing a nitrogen atom and additionally 1 to 3heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom, such as pyrrolidine, pyrroline, imidazolidine,imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine,oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine,azacycloheptane, azacyclooctane (azocane), etc.; or the like, and thesenitrogen-containing heterocyclic rings may be bridged via a straightatomic chain having 1 or 2 carbon atoms, forming a bridged-ringnitrogen-containing heterocyclic ring such as azabicyclo[2.2.1]heptane,azabicyclo[2.2.2]octane (quinuclidine), etc. (preferably, piperidinebridged via a straight atomic chain having 1 or 2 carbon atoms, etc.).

Among specific examples of the above-described nitrogen-containingheterocyclic ring, preferred are pyridine, pyridazine, pyrazole,imidazole, triazole, tetrazole, imidazopyridine, pyrrolidine,piperidine, piperazine, morpholine, thiomorpholine and azabicyclo[2.2.2]octane (preferably, pyridine, imidazole, triazole, imidazopyridine,pyrrolidine, piperidine and morpholine).

The nitrogen atom of the “nitrogen-containing heterocyclic ring” may beconverted to a quaternary ammonium or an oxide. When the nitrogen atomof the “nitrogen-containing heterocyclic ring” is converted to aquaternary ammonium, the counter anion of the “nitrogen-containingheterocyclic group, in which the nitrogen atom is converted to aquaternary ammonium” may be exemplified by, in addition to anions ofhalogen (for example, Cl⁻, Br⁻, I⁻, etc.), anions derived from inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; anions derived from organic acids such asformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; anions derived from acidic amino acids such as asparticacid, glutamic acid, etc.; and the like, and among them, Cl⁻, Br⁻, I⁻and the like are preferred.

The “nitrogen-containing heterocyclic group” may be bonded to a divalentgroup represented by Z² via a carbon atom or a nitrogen atom, and may bebonded to a ring-constituting carbon atom as in 2-pyridyl, 3-pyridyl,2-piperidinyl, etc., or to a ring-constituting nitrogen atom as in thefollowing:

The substituent which may be carried by the “nitrogen-containingheterocyclic ring” may be exemplified by halogen (for example, fluorine,chlorine, bromine, iodine, etc.), lower (C₁₋₄) alkyl which may besubstituted, lower (C₁₋₄) alkoxy which may be substituted, phenyl whichmay be substituted, monophenyl- or diphenyl-lower (C₁₋₄) alkyl which maybe substituted, C₃₋₇ cycloalkyl which may be substituted, cyano, nitro,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., andthe like); carboxyl group which may be esterified or amidated (forexample, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.); lower (C₁₋₄)alkoxy-carbonyl; formyl; lower (C₂₋₄) alkanoyl; lower (C₁₄)alkylsulfonyl; a heterocyclic group which may be substituted (forexample, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom such as furan, thiophene, pyrrole, imidazole,pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole,pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole,thiadiazole, etc.); a group formed by eliminating one hydrogen atom forma fused aromatic heterocyclic ring containing 1 to 4 heteroatoms of oneor two kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom, such as benzofuran, indole, benzothiophene, benzoxazole,benzothiazole, indazole, benzimidazole, quinoline, isoquinoline,quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc.;a group formed by eliminating one hydrogen atom from a 5- to 6-memberednon-aromatic heterocyclic ring containing 1 to 4 heteroatoms of one ortwo kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom, such as tetrahydrofuran, tetrahydrothiophene, dithiolane,oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, tetrahydrothiopyran, etc.; and the like, and the numberof the substituents is preferably 1 to 3. The nitrogen atom in the“nitrogen-containing heterocyclic ring” may be oxidized.

Examples of the substituent which may be carried by the “lower (C₁₋₄)alkyl which may be substituted”, the “lower (C₁₋₄) alkoxy which may besubstituted”, the “phenyl which may be substituted”, the “monophenyl- ordiphenyl-lower (C₁₋₄) alkyl which may be substituted”, the “C₃₋₇cycloalkyl which may be substituted”, and the “heterocyclic group whichmay be substituted”, all of which are the substituents which may becarried by the “nitrogen-containing heterocyclic ring”, include halogen(for example, fluorine, chlorine, bromine, iodine, etc.); lower (C₁₋₄)alkyl which may be halogenated; lower (C₁₋₄) alkyl which may besubstituted with a polar group such as hydroxy group, cyano group,carboxyl group which may be esterified or amidated, etc. (for example,hydroxy C₁₋₄ alkyl, cyano C₁₋₄ alkyl, carboxyl C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl C₁₋₄ alkyl, carbamoyl C₁₋₄ alkyl, mono-C₁₋₄alkylcarbamoyl C₁₋₄ alkyl, di-C₁₋₄ alkylcarbamoyl C₁₋₄ alkyl,pyrrolidinocarbonyl C₁₋₄ alkyl, piperidinocarbonyl C₁₋₄ alkyl,morpholinocarbonyl C₁₋₄ alkyl, thiomorpholinocarbonyl C₁₋₄ alkyl, etc.);lower (C₃₋₁₀) cycloalkyl; lower (C₃₋₁₀) cycloalkenyl; C₁₋₄ alkoxy whichmay be halogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.); formyl; C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.); C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.); C₁₋₃ alkylenedioxy (for example, methylenedioxy,ethylenedioxy, etc.); cyano; nitro; hydroxy group; thiol group which maybe substituted (for example, thiol, C₁₋₄ alkylthio groups, etc.); aminogroup which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., and the like); carboxyl group which may beesterified or amidated (for example, carboxyl, C₁₋₄ alkoxy-carbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.);lower (C₁₋₄) alkoxycarbonyl; and the like, and the number of thesubstituents is preferably 1 to 3.

In the above formula (I), examples of the substituent which may becarried by the “nitrogen-containing heterocyclic ring” of the“nitrogen-containing heterocyclic ring of the heterocyclic ring whichmay be substituted and which may contain a sulfur atom or an oxygen atomas a ring-constituting atom, in which the nitrogen atom may be convertedto a quaternary ammonium or an oxide” preferably include (1) halogen,(2) cyano, (3) hydroxy group, (4) carboxyl group, (5) carbamoyl group,(6) lower (C₁₋₄) alkoxy-carbonyl, (7) lower (C₁₋₄) alkylcarbamoyl or 5-or 6-membered cyclic amino (e.g., piperidino, morpholino,etc.)-carbonyl, (8) lower (C₁₋₄) alkyl which may be substituted withhalogen, hydroxy group, cyano group, lower (C₁₋₄) alkoxy, or carboxylwhich may be esterified or amidated, (9) lower (C₁₋₄) alkoxy which maybe substituted by halogen, hydroxy group or lower (C₁₋₄) alkoxy, (10)phenyl which may be substituted by halogen, lower (C₁₋₄) alkyl, hydroxygroup, lower (C₁₋₄) alkoxy or C₁₋₃ alkylenedioxy, (11) monophenyl- ordiphenyl-lower (C₁₋₄) alkyl which may be substituted with halogen, lower(C₁₋₄) alkyl, hydroxy group, lower (C₁₋₄) alkoxy or C₁₋₃ alkylenedioxy,(12) a group formed by eliminating one hydrogen atom form a 5- or6-membered aromatic heterocyclic ring such as furan, thiophene, pyrrole,pyridine, etc., and the like.

In the group represented by the formula (a) of R² in the above formula(I), examples of the “hydrocarbon group which may be substituted”represented by R⁵ and R⁶ include:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, and the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., and the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbons such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl, and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbons such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., and the like);

(5) alkynyl which may be substituted (for example, alkynyl having 2 to10 carbons such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-pentynyl, 3-hexynyl, etc., preferably lower (C₂₋₆) alkynyl, and thelike);

(6) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.), and the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like. Examples of the substituent which may be carried by theabove-described (1) alkyl which may be substituted, (2) cycloalkyl whichmay be substituted, (3) alkenyl which may be substituted, (4)cycloalkenyl which may be substituted, (5) alkynyl which may besubstituted, (6) aralkyl which may be substituted, and (7) aryl whichmay be substituted include halogen (for example, fluorine, chlorine,bromine, iodine, etc.); nitro; cyano; hydroxy group; thiol group whichmay be substituted (for example, thiol, C₁₋₄ alkylthio, etc.); aminogroup which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., and the like); carboxyl group which may beesterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc,); C₁₋₄alkyl which may be halogenated (for example, trifluoromethyl, methyl,ethyl, etc.); C₁₋₄ alkoxy which may be halogenated (for example,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.); formyl; C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.); C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.); and the like, and thenumber of the substituents is preferably 1 to 3.

Examples of the “hydroxy group which may be substituted” represented byR⁵ and R⁶ include hydroxy group which may have a substituent selectedfrom:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, and the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., and the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbons such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl, and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbons such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., and the like);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.) and the like);

(6) formyl or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbons (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbons (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) aralkyl which may be substituted, (6) acylwhich may be substituted, and (7) aryl which may be substituted includehalogen (for example, fluorine, chlorine, bromine, iodine, etc.); nitro;cyano; hydroxy group; thiol group which may be substituted (for example,thiol, C₁₋₄ alkylthio, etc.); amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., andthe like); carboxyl group which may be esterified or amidated (forexample, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc,); C₁₋₄ alkyl which may behalogenated (for example, trifluoromethyl, methyl, ethyl, etc.); C₁₋₄alkoxy which may be halogenated (for example, methoxy, ethoxy,trifluoromethoxy, trifluoroethoxy, etc.); formyl; C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.); C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.); and the like, and the number ofthe substituents is preferably 1 to 3.

In the above formula, R⁵ and R⁶ may be bonded to each other to form aring together with the adjacent phosphorus atom (preferably, a 5- to7-membered ring). Such ring may be substituted and examples of thesubstituent include halogen (for example, fluorine, chlorine, bromine,iodine, etc.); nitro; cyano; hydroxy group; thiol group which may besubstituted (for example, thiol, C₁₋₄ alkylthio, etc.); amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., and the like); carboxyl group which may beesterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc,); C₁₋₄alkyl which may be halogenated (for example, trifluoromethyl, methyl,ethyl, etc.); C₁₋₄ alkoxy which may be halogenated (for example,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.); formyl; C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.); C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.); and the like, and thenumber of the substituents is preferably 1 to 3.

In the above formula (I), when the phosphorus atom forms a phosphoniumsalt, examples of the counter anion include, in addition to anions ofhalogen (for example, Cl⁻, Br⁻, I⁻, etc.), anions derived from inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; anions derived from organic acids such asformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; and anions derived from acidic amino acids such as asparticacid, glutamic acid, etc., and among them, Cl⁻, Br⁻, I⁻ and the like arepreferred.

Examples of amino group which may be substituted represented by R⁵ andR⁶ include amino group which may have 1 or 2 substituents selected from:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, and the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., and the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbons such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably lower (C₂₋₆) alkenyl and the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbons such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., and the like);

(5) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbons (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), and alkylsulfonyl having 1 to 4 carbons (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) acyl which may be substituted, and (6)aryl which may be substituted include halogen (for example, fluorine,chlorine, bromine, iodine, etc.); nitro; cyano; hydroxy group; thiolgroup which may be substituted (for example, thiol, C₁₋₄ alkylthio,etc.); amino group which may be substituted (for example, amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., and the like); carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc,); C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl, etc.); C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.); formyl; C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.); C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.); and the like, and the number of the substituentsis preferably 1 to 3.

The substituent of the “amidino group which may be substituted” and the“guanidino group which may be substituted” represented by R² may be thesame substituent as that of the “amino group which may be substituted,in which the nitrogen atom may be converted to a quaternary ammonium oran oxide” represented by R² above.

R² is preferably (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium or an oxide;(2) a nitrogen-containing heterocyclic group which may be substitutedand may contain a sulfur atom or an oxygen atom as a ring-constitutingatom, in which the nitrogen atom may be converted to a quaternaryammonium or an oxide; (3) an amidino group which may be substituted; or(4) a guanidino group which may be substituted; R² is more preferablythe amino group which may be substituted, in which the nitrogen atom maybe converted to a quaternary ammonium; and the nitrogen-containingheterocyclic group which may be substituted and which may contain asulfur atom or an oxygen atom as the ring-constituting atom and whichmay be an oxide, and particularly preferably the amino group which maybe substituted, the nitrogen-containing heterocyclic group which may besubstituted and may contain a sulfur atom or an oxygen atom as thering-constituting atom, etc.

R² is further more preferably a group of the formula —NRR″ or —N⁺RR′R″(wherein, R, R′ and R″ are each an aliphatic hydrocarbon group (achained aliphatic hydrocarbon group or a cyclic aliphatic hydrocarbongroup) or an alicyclic (non-aromatic) heterocyclic group which may besubstituted), or a nitrogen-containing aromatic heterocyclic group whichmay be substituted, in which the nitrogen atom may be converted to anoxide.

The “aliphatic hydrocarbon group which may be substituted” and “thealicyclic heterocyclic group which may be substituted” represented by R,R′ and R″ in the above formula may be the same “aliphatic hydrocarbongroup which may be substituted (for example, alkyl, cycloalkyl, alkenyl,cycloalkenyl, etc., each of which may be substituted)” and the“alicyclic heterocyclic group which may be substituted (for example, 5-or 6-membered non-aromatic heterocyclic ring which may be substituted,etc.)” as those exemplified with respect to the substituent which may becarried by the “amino group which may be substituted” represented by R².

Among them, each of R and R′ is preferably a chained hydrocarbon groupwhich may be substituted (for example, alkyl, alkenyl, etc., each ofwhich may be substituted), more preferably C₁₋₆ alkyl which may besubstituted, and particularly preferably methyl which may besubstituted.

R″ is preferably an alicyclic hydrocarbon group which may be substituted(preferably, C₃₋₈ cycloalkyl which may be substituted, and morepreferably cyclohexyl which may be substituted), or an alicyclicheterocyclic group which may be substituted (preferably, a saturatedalicyclic heterocyclic group (preferably, a 6-membered ring) which maybe substituted; more preferably, tetrahydropyranyl which may besubstituted, tetrahydrothiopyranyl which may be substituted, orpiperidyl which may be substituted; and particularly preferablytetrahydropyranyl which may be substituted).

The “nitrogen-containing aromatic heterocyclic group” of the“nitrogen-containing aromatic heterocyclic group which may besubstituted, in which the nitrogen atom may be converted to an oxide”represented by R² includes preferably pyridine, imidazole, triazole, andimidazopyridine, particularly imidazole and triazole being preferred.

Examples of the “amino group which may be substituted, in which thenitrogen atom may be converted to a quaternary ammonium or an oxide”,etc. represented by R^(2′) and R^(2″) include the corresponding samegroups as those exemplified with respect to the above R², respectively.

The following compounds are preferred examples of the compoundrepresented by the formula (I):

3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8-dihydropyrido[2,3-b]azepine-6-carboxamide;

3-[4-(2-butoxyethoxy)phenyl]-9-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8-dihydropyrido[2,3-b]azepine-6-carboxamide;

(S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

(S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;

(S)-3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8-dihydropyrido[2,3-b]azepine-6-carboxamide;

(S)-3-[4-(2-butoxyethoxy)phenyl]-9-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8-dihydropyrido[2,3-b]azepine-6-carboxamide;

3-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide;and the like.

A salt of the compound represented by the formula (I) of the presentinvention is preferably a pharmaceutically acceptable salt. Examples ofthe salt include salts with inorganic bases, salts with organic bases,salts with inorganic acids, salts with organic acids, salts with basicor acidic amino acids; and the like. Suitable examples of the salts withthe inorganic bases include alkali metal salts such as a sodium salt, apotassium salt, etc.; alkaline earth metal salts such as a calcium salt,a magnesium salt, etc.; an aluminum salt; an ammonium salt; etc.Suitable examples of the salts with the organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc. Suitable examples of the salts withthe inorganic acids include salts with hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitableexamples of the salts with the organic acids include salts such asformate, acetate, trifluoroacetate, fumarate, oxalate, tartrate,maleate, citrate, succinate, malate, methanesulfonate, benzenesulfonate,p-toluenesulfonate, etc. Suitable examples of the salts with basic aminoacids include salts with arginine, lysine, ornithine, etc. Suitableexamples of the salts with acidic amino acids include salts withaspartic acid, glutamic acid, etc. The compound represented by theformula (I) of the present invention may be either a hydrate or anon-hydrate. When the compound represented by the formula (I) of thepresent invention is present as a mixture of configurational isomers,diastereomers, or conformers, the compound may be isolated by separationand purification methods known in the art, if desired. When the compoundrepresented by the formula (I) is present as a racemate, each of (S) and(R) isomers may be separated by general means for optical resolution.Each of the optical isomers as well as the racemate is included in thescope of the present invention.

The prodrug of the compound represented by formula (I) used in theinvention or a salt thereof [hereinafter, may be sometimes referred toas Compound (I)] refers to a compound which is converted to Compound (I)by an in vivo reaction caused by an enzyme, gastric acid or the likeunder physiological conditions, that is, a compound which is convertedto Compound (I) upon occurrence of enzymatic oxidation, reduction,hydrolysis or the like, or a compound which is converted to Compound (I)upon occurrence of hydrolysis or the like by gastric acid or the like.The prodrug of Compound (I) may be exemplified by compounds resultingfrom acylation, alkylation or phosphorylation of the amino group ofCompound (I) (for example, the compounds in which the amino group ofCompound (I) is in the form of eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl or the like); compoundsresulting from acylation, alkylation, phosphorylation or boration of thehydroxy group of Compound (I) (for example, the compounds in which thehydroxy group of Compound (I) is in the form of acetyl, palmitoyl,propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl or the like); compounds resulting fromesterification or amidation of the carboxyl group of Compound (I) (forexample, the compounds in which the carboxyl group of Compound (I) is inthe form of ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide or the like); or thelike. These compounds can be prepared from Compound (I) by methods knownper se in the art.

Furthermore, the prodrug of Compound (I) may be also a compound which isconverted to Compound (I) under physiological conditions, as describedin “Development of Pharmaceutical Products”, Vol. 7 Design of Molecules,Hirokawa Publisher, pp. 163-198 (1990).

Also, Compound (I) may be labeled with isotopes (for example, ³H, ⁴C,³⁵S, ¹²⁵I, etc.).

Hereinafter, a process for producing the compound represented by theformula (I) or a salt thereof will be explained.

The compound represented by the formula (I) or the salt thereof can beproduced by processes known per se. For example, it can be produced bythe following processes. Alternatively, the compound represented by theformula (I) or the salt thereof may be produced by the process describedin JP-A No. 8-73476 or a similar method thereto.

The compounds which will be used in each of the following processes mayform salts similar to the salt of Compound (I), as far as the salts donot interfere with the reactions.

Further, in the following reactions, when the starting compounds haveamino, carboxyl or hydroxy groups as substituents, these groups may beprotected by protective groups which are commonly used in peptidechemistry, and if necessary, the protective groups can be removed afterthe reactions to obtain desired compounds.

Examples of the protective group for an amino group include a C₁₋₆alkylcarbonyl which may be substituted (for example, acetyl, propionyl,etc.), formyl, phenylcarbonyl, a C₁₋₆ alkyloxycarbonyl (for example,methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.),phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), a C₇₋₁₀aralkyloxycarbonyl (for example, benzyloxycarbonyl, etc.), trityl,phthaloyl and the like. The substituents of these protective groupsinclude a halogen atom (for example, fluorine, chlorine, bromine,iodine, etc.), a C₁₋₆ alkylcarbonyl (for example, acetyl, propionyl,butyryl, etc.), a nitro group and the like, and the number of-thesubstituents is about 1 to 3.

Examples of the protective group to be used for a carboxyl group includea C₁₋₆ alkyl which may be substituted (for example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl andthe like. The substituents of these protective groups include a halogenatom (for example fluorine, chlorine, bromine, iodine, etc.), a C₁₋₆alkylcarbonyl (for example, acetyl, propionyl, butyryl, etc.), formyl, anitro group and the like, and the number of the substituents is about 1to 3.

Examples of the protective groups to be used for a hydroxy group includea C₁₋₆ alkyl which may be substituted (for example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C₇₋₁₀ aralkyl (forexample, benzyl, etc.), a C₁₋₆ alkylcarbonyl (for example, acetyl,propionyl, etc.), formyl, phenyloxycarbonyl, a C₇₋₁₀ aralkyloxycarbonyl(for example, benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl and thelike. The substituents of these protective groups include a halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.), a C₁₋₆ alkyl,phenyl, a C₇₋₁₀ aralkyl, a nitro group and the like, and the number ofthe substituents is about 1 to 4.

Introduction and removal of protective groups are carried out accordingto methods known per se or similar methods thereto [for example, themethod described in “Protective Groups in Organic Chemistry”, (J. F. W.McOmie et al., Plenum Press)], and removal is carried out by, forexample, a method comprising treating with an acid, a base, reduction,ultraviolet light, hydrazine, phenylhydrazine, sodiumN-methydithiocarbamate, tetrabutylammonium fluoride, palladium acetate,or the like.

In the following description, the compounds represented by the formulas(I), (Ia), (Ib), (II) and (III) including their salts may be also simplyreferred to as Compound (I), Compound (Ia), Compound (Ib), Compound (II)and Compound (III).

[Process A]

Compound (I) can be prepared by reacting Compound (II) with Compound(III) according to the following reaction:

wherein each symbol has the same meaning as defined above.

In this reaction, a carboxylic acid derivative (II) is reacted with anamine derivative (III) to prepare Compound (I).

The condensation reaction of Compound (II) and Compound (III) isconducted by a conventional means for peptide synthesis. The means forpeptide synthesis may be carried out according to any method known inthe art, for example, the methods described in M. Bodansky and M. A.Ondetti, Peptide Synthesis, Interscience, New York (1966); F. M. Finnand K. Hofmann, The Proteins, Vol. 2; H. Nenrath and R. L. Hill, Ed.,Academic Press Inc., New York (1976); and Nobuo Izumiya et al.Foundations and Experiments in Peptide Synthesis, Maruzen Co. (1985) andthe like, which include, for example, azide method, chloride method,acid anhydride method, mixed acid anhydride method, DCC method,activated ester method, method using Woodward's reagent K,carbonyldiimidazole method, oxidation/reduction method, DCC/HONB method,as well as WSC method, diethyl cyanophosphate (DEPC) method and thelike. In other words, examples of the reactive derivatives that may beused include acid halides (for example, acid chloride, acid bromide,etc.), acid azides, acid anhydrides, mixed acid anhydrides [for example,mixed acid anhydrides of a mono-C₁₋₆ alkylcarbonic acid (for example,mixed acid anhydrides of a free acid with monomethylcarbonic acid,monoethylcarbonic acid, monoisopropylcarbonic acid, monoisobutylcarbonicacid, mono-tert-butylcarbonic acid, monobenzylcarbonic acid,mono(p-nitrobenzyl)carbonic acid, or monoallylcarbonic acid, etc.),mixed acid anhydrides of a C₁₋₆ aliphatic carboxylic acid (for example,mixed acid anhydrides of a free acid with acetic acid, trichloroaceticacid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid,trichloroacetic acid, acetoacetic acid, etc.), mixed acid anhydrides ofa C₇₋₁₂ aromatic carboxylic acid (for example, mixed acid anhydrides ofa free acid with benzoic acid, p-toluic acid, p-chlorobenzoic acid,etc.), mixed acid anhydrides of organic sulfonic acid (for example,mixed acid anhydrides of a free acid with methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.)etc.], activated amides, activated esters (for example,diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, etc.), activatedthioesters (for example, 2-pyridylthiol ester, 2-benzothiazolylthiolester, etc.) and the like. This condensation reaction can be carried outin a solvent. Examples of the solvent include N,N-dimethylformamide,dimethylsulfoxide, pyridine, chloroform, dichloromethane,tetrahydrofuran, dioxane, acetonitrile, each of which is dehydrated orhydrated, or appropriate mixtures thereof. The reaction temperature isusually about −20° C. to about 50° C., and preferably about −10° C. toabout 30° C. The reaction time is about 1 to about 100 hours, andpreferably about 2 to about 40 hours. The thus-obtained Compound (I) canbe isolated and purified by known separation and purification means suchas concentration, vacuum concentration, solvent extraction,crystallization, recrystallization, redissolution, chromatography or thelike.

(1) When R^(2a) as represented in Compound (I-1) is, for example, atertiary amine residue, Compound (I-1) can be reacted with an alkylhalide or an aralkyl halide to prepare a quaternized Compound (I′).Herein, examples of the halogen atom include chlorine, bromine, iodine,etc., and the alkyl halide (for example, lower (C₁₋₆) alkyl halide,etc.), or the aralkyl halide (for example, lower (C₁₋₄) alkyl-phenylhalide, etc.) is typically used in an amount of about 1 to 5 moles withrespect to 1 mole of Compound (I-1). The reaction can be carried out inan inert solvent, for example, toluene, benzene, xylene,dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide(DMF), dimethylacetamide, etc., or a mixture of the solvents above. Thereaction temperature is in a range of about 10° C. to about 160° C., andpreferably about 20° C. to about 120° C. The reaction time is about 1 toabout 100 hours, and preferably about 2 to about 40 hours. The reactionis preferably carried out under an inert gas atmosphere (for example,nitrogen, argon, etc.).

(2) When R^(2a) as represented in Compound (I-1) is, for example, asecondary amine residue, Compound (I-1) can be reacted with an alkylhalide or an aralkyl halide to prepare a tertiarized Compound (I′).Herein, examples of the halogen atom include chlorine, bromine, iodine,etc., and the alkyl halide or aralkyl halide is typically used in anamount of about 1 to 2 moles with respect to 1 mole of Compound (I-1).The reaction can be facilitated, if necessary, by addition of about anequimolar amount to about three-fold moles of a base such astriethylamine, diisopropylethylamine, pyridine, lithium hydride, sodiumhydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate or the like, and by further addingsodium iodide, potassium iodide, or the like.

This reaction of tertiary amination can be carried out in an inertsolvent such as methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature ranging from about 0° C. to about 180° C. for about 1 toabout 40 hours. Also, the reaction is preferably carried out under aninert gas atmosphere (for example, nitrogen, argon, etc.).

(3) When R^(2a) as represented in Compound (I-1) is, for example, asecondary amine residue, Compound (I-1) can be reacted with an aldehydecompound in the presence of a reductive amino reagent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, sodium borohydride orthe like to prepare a tertiarized Compound (I′). The reaction conditionsfor this reductive amination reaction are preferably changed dependingon the reagent used. For example, when sodium triacetoxyborohydride isused, the reaction can be conducted in an inert solvent, for example,dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran (THF),diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF), etc., ora mixture of the solvents above. The reagent is used in an amount ofabout 1 to 2 molar equivalents with respect to 1 mole of Compound (I-1).The reaction is usually carried out at a temperature ranging from about0° C. to about 80° C. for about 1 to about 40 hours. The reaction ispreferably carried out under an inert gas atmosphere (for example,nitrogen, argon, etc.).

(4) When R^(2a′) as represented in Compound (I-1) is, for example, asulfide residue or a tertiary amine residue, or when Z² is, for example,a sulfide residue, Compound (I-1) can be reacted with an oxidizingagent, for example, m-chloroperbenzoic acid, perbenzoic acid,p-nitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid,hydrogen peroxide, sodium periodate, potassium periodate, etc., toprepare Compound (I′) having a sulfinyl group, a sulfonyl group or anamine oxide group. The reaction conditions for this oxidation reactionare preferably changed depending on the oxidizing agent used. Forexample, when m-chloroperbenzoic acid is used, the reaction can becarried out in an inert solvent, for example, dichloromethane,chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, acetone,ethyl acetate, etc., or a mixture of the solvents above. The oxidizingagent is used in an amount of about 1 to 3 molar equivalents withrespect to 1 mole of Compound (I-1). The reaction is usually carried outat a temperature ranging from about −78° C. to about 80° C. (preferablyfrom −50 to 25° C.), for about 1 to about 40 hours.

When Z² as represented in Compound (I-1) is, for example, a sulfideresidue, Compound (I′) having an optically active sulfinyl group can beprepared according to the methods known per se, for example, the methoddescribed in Ojima, I., Ed., Catalytic Asymmetric Synthesis, 2000,Wiley-VCH (New York), or a similar method thereto.

V in Compound (IV) represents a halogen atom (chlorine, bromine, iodine,etc.), or a sulfonyloxy group (a methanesulfonyloxy group, atrifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, atoluenesulfonyloxy group, etc.), and the other symbols have the samemeanings as defined above.

(1) Compound (IV) can be reacted with a tertiary amine to preparequaternized Compound (I′). This reaction can be carried out in an inertsolvent, for example, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, dimethylformamide (DMF),dimethylacetamide, etc., or a mixture of the solvents above. Thetertiary amine is used in an amount of about 1 to 3 moles with respectto 1 mole of Compound (IV). This reaction is carried out at atemperature in a range of about 10° C. to about 120° C. for about 1 toabout 40 hours. The reaction is preferably carried out under an inertgas (for example, nitrogen, argon, etc.) atmosphere.

(2) Compound (IV) can be reacted with a tertiary phosphine to preparequaternized Compound (I′). This reaction can be carried out in an inertsolvent, for example, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF),etc., or a mixture of the solvents above. The tertiary phosphine is usedin an amount of about 1 to 2 moles with respect to 1 mole of Compound(IV). This reaction is carried out at a temperature in a range of about20° C. to about 150° C. for about 1 to about 50 hours. This reaction ispreferably carried out under an inert gas (for example, nitrogen, argon,etc.) atmosphere.

(3) Compound (IV) can be reacted with a primary or secondary aminecompound or a thiol compound to prepare Compound (I′) having a secondaryor tertiary amino group or a thio group. The primary or secondary aminecompound or the thiol compound is usually used in an amount of about 1to 3 moles with respect to 1 mole of Compound (IV). This reaction can befacilitated, if necessary, by adding about an equivalent to three-foldmoles of a base such as triethylamine, diisopropylethylamine, pyridine,lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide,sodium carbonate, potassium carbonate, sodium hydrogen carbonate and thelike, and by further adding sodium iodide, potassium iodide and thelike. This substitution reaction can be carried out in an inert solvent,for example, methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature in a range of about −10° C. to about 180° C. for about 1 toabout 40 hours. This reaction is preferably carried out under an inertgas (for example, nitrogen, argon, etc.) atmosphere.

(1) Compound (V) [wherein V′ represents a halogen atom (bromine, iodine,etc.) or a sulfonyloxy group (a trifluoromethanesulfonyloxy group,etc.), and the other symbols have the same meanings as defined above]can be subjected to, for example, the Suzuki reaction [across-condensation reaction of an arylboric acid and, for example, arylhalide or aryloxy trifluoromethanesulfonate, catalyzed by a palladiumcatalyst; A. Suzuki et al., Synth. Commun., 11, 513 (1981)), to prepareCompound (I′) in which R^(1′) is a 5- or 6-membered aromatic group. Thearylboric acid can be used in an amount of about an equivalent to1.5-fold moles with respect to 1 mole of Compound (V) to prepareCompound (I″).

Further, Compound (V) can be subjected to, for example, across-condensation reaction with an arylacetylene compound in thepresence of a palladium catalyst[dichlorobis(triphenylphosphine)palladium, etc.] [K. S. Y. Lau et al.,J. Org. Chem., 46, 2280 (1981); J. W. Tilley, S. Zawoisky et al., J.Org. Chem., 53, 386 (1988)] to prepare Compound (I″) having an acetylenebond, in which X¹ represents —C≡C—. The arylacetylene compound can beused typically in an amount of about an equivalent to two-fold moleswith respect to 1 mole of Compound (V) to prepare Compound (I″).

(2) Compound (V) [wherein V′ represents a hydroxy group and the othersymbols have the same meanings as defined above] can be subjected to,for example, the Mitsunobu reaction [an etherification reaction using,for example, triphenylphosphine and diethyl azodicarboxylate as thecondensing agents; O. Mitsunobu et al., Synthesis, 1 (1981)] to prepareCompound (I″) having an ether bond. The corresponding alcohol compoundor phenol compound can be used in an amount of about an equivalent tothree-fold moles with respect to 1 mole of Compound (V) to prepareCompound (I″).

Compound (I″) having an ether bond can also be prepared by anetherification reaction of Compound (V) with a reactive compound such asa halide (chloride, bromide, iodide, etc.) compound, a tosylatecompound, a mesylate compound, etc. The reactive compound is usedtypically in an amount of about an equivalent to two-fold moles withrespect to 1 mole of Compound (V). This reaction can be facilitated, ifnecessary, by adding about an equivalent to three-fold moles of a basesuch as triethylamine, diisopropylethylamine, pyridine, lithium hydride,sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide,sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc., and by further adding sodium iodide, potassium iodide,etc. The reaction can be carried out in an inert solvent such astetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature in a range of about −10° C. to 180° C. for about 1 to about40 hours. The reaction is preferably carried out under an inert gas (forexample, nitrogen, argon, etc.) atmosphere.

(3) Compound (V), wherein V′ represents a carbonyl group which may besubstituted, a phosphonium salt or a phosphonic acid ester residue, andthe other symbols have the same meanings as defined above, can besubjected to, for example, the Wittig reaction [A. Maercker, Org.React., 14, 270 (1965)] or the Wittig-Horner-Emmons reaction [J. Boutagyand R. Thomas, Chem. Rev., 74, 87 (1974)] to prepare Compound (I″)having a vinyl bond. The corresponding carbonyl compound, a phosphoniumsalt or a phosphonic acid ester compound is used in an amount of aboutan equivalent to 1.5-fold moles with respect to 1 mole of Compound (V).

(1) First, Compound (VI), wherein V″ represents a cyano group, and theother symbols have the same meanings as defined above, is reacted with alower alcohol such as methanol, ethanol, propanol, etc. in the presenceof an acid such as hydrochloric acid, etc. to give an imidate compound.This reaction is typically carried out using an excess of the alcohol ata temperature in a range of about −10° C. to 50° C. for about 1 hour toabout 40 hours. The reaction can be carried out in an inert solvent suchas diethyl ether, 1,4-dioxane, toluene, benzene, xylene,dichloromethane, chloroform, 1,2-dichloroethane, etc., or a mixture ofthe solvents above.

Subsequently, the resulting imidate compound can be subjected to asubstitution reaction with a primary or secondary amine compound toprepare an amidine compound [I′″]. The primary or secondary aminecompound is used typically in an amount of about 1 to 5 moles withrespect to 1 mole of the imidate compound. The reaction can befacilitated, if necessary, by adding about an equimolar amount tothree-fold moles of a demineralizing agent such as triethylamine,pyridine, sodium hydroxide, potassium hydroxide, sodium methoxide,sodium ethoxide, sodium carbonate, potassium carbonate, etc. Thissubstitution reaction can be carried out in an inert solvent, forexample, methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature in a range of about 0° C. to 150° C. for about 1 to about 50hours. The reaction is also preferably carried out under an inert gas(for example, nitrogen, argon, etc.) atmosphere.

(2) Compound (VI), wherein V″ is an amino group, and the other symbolshave the same meanings as defined above, can be subjected to asubstitution reaction with an S-alkyl (for example, methyl, ethyl,etc.)-isothiourea compound to prepare guanidine Compound (I′″). TheS-alkyl-isothiourea compound is typically used in an amount of about anequivalent to two-fold moles with respect to 1 mole of Compound (VI).This reaction can be facilitated, if necessary, by adding about anequimolar amount to three-fold moles of a demineralizing agent such astriethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, sodium carbonate, potassium carbonate, etc.This substitution reaction can be carried out in an inert solvent, forexample, methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature in a range of about 0° C. to 150° C. for about 1 to about 50hours. This reaction is preferably carried out under an inert gas (forexample, nitrogen, argon, etc.) atmosphere.

The thus-obtained Compound (I) can be isolated and purified by knownseparation and purification means, for example, concentration, vacuumconcentration, solvent extraction, crystallization, recrystallization,redissolution, chromatography and the like.

Compound (II-1) which is used as the starting material can be preparedby any known methods (for example, the methods described in JP-A No.8-73476; and JP-A No. 2001-058988, etc.) or a modification thereof, forexample, the method of the reaction scheme I, the methods in ReferenceExamples described below and modifications thereof.

wherein R⁹ and R¹⁰ each represents a C₁₋₄ alkyl group, X¹ represents aleaving group [a halogen atom (chlorine, bromine, iodine, etc.),methanesulfonyloxy, trifluoromethanesulfonyl, benzenesulfonyloxy,toluenesulfonyloxy, etc.], Y″ represents a divalent group having nounsaturated bond, in which a Y″-containing ring forms a 6- to10-membered ring, and the other symbols have the same meanings asdefined above.

Compound (VII) can be subjected to the Dieckmann (type) condensationreaction (J. P. Schaefer and J. J. Bloomfield, Org. Reactions, 15, 1(1967)) to prepare Compound (VIII) or Compound (IX). Compound (VIII) canbe subjected to catalytic hydrogenation or a reductive reaction withsodium borohydride, etc. to prepare Compound (IX). Compound (IX) can besubjected to dehydration by a conventional method to prepare anunsaturated carboxylic ester (X). Compound (X) can be subjected to, forexample, the Suzuki reaction and subsequently subjected to esterhydrolysis to prepare unsaturated carboxylic acid Compound (II′).

Also, Compound (III-1) can be prepared by any known methods (forexample, the methods described in JP-A No. 8-73476, etc.) or similarmethods thereto, for example, the method of the reaction scheme III, themethods in Reference Examples described below and modifications thereof.

wherein each symbol has the same meaning as defined above.

Reduction of Compound (XII) can be carried out by the methods known perse in the art. For example, reduction by metal, metal hydride or a metalhydrogen complex compound, reduction by diborane and substituted borane,catalytic hydrogenation, or the like is used. That is, this reaction iscarried out by treating Compound (XII) with a reducing agent. Examplesof the reducing agent include metals such as reduced iron, zinc powder,etc.; metal hydrogen complex compounds such as alkali metal borohydrides(for example, sodium borohydride, lithium borohydride, etc.), aluminumlithium hydride, etc.; metal hydrides such as sodium hydride, etc.;organic tin compounds (triphenyltin hydride, etc.); metals and metalsalts such as nickel compounds, zinc compounds, etc.; catalytic reducingagents using hydrogen and transition metal catalysts such as palladium,platinum, rhodium, etc.; diborane; and the like. The catalytic reductionusing hydrogen and a transition metal such as palladium, platinum,rhodium, etc., and the reduction by a metal such as reduced iron areadvantageously employed. This reaction is carried out in an organicsolvent which does not interfere with the reaction. The solvent isappropriately selected for use from, for example, benzene, toluene,xylene, chloroform, carbon tetrachloride, dichloromethane,1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether,tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol,2-methoxyethanol, N,N-dimethylformamide, acetic acid or a mixture of thesolvents above, depending on the kind of the reducing agent. Thereaction temperature is about −20° C. to about 150° C., and particularlypreferably about 0° C. to about 100° C., and the reaction time is about1 to about 24 hours.

The thus-obtained Compound (III-1) can be isolated and purified by knownseparation and purification means such as concentration, vacuumconcentration, solvent extraction, crystallization, recrystallization,redissolution, chromatography and the like.

The compound represented by the formula (I) of the present invention ora salt thereof including the above-mentioned Compound (Ia), Compound(I-1), Compound (I′), Compound (I″) and Compound (I′″) (hereinafter, inthe case where it is briefly referred to as “the compound represented bythe formula (I)”, it is intended to include a salt thereof and thecompound represented by the formula (I) and a salt thereof) can beadministered orally or parenterally alone or as a pharmaceuticalcomposition comprising the compound mixed with a pharmaceuticallyacceptable carrier in the form of a solid preparation such as a tablet,a capsule, a granule, powders, etc., or a liquid preparation such as asyrup, an injectable solution, etc.

Examples of the dosage form for parenteral administration include aninjectable solution, an infusion, a suppository, a vaginal suppository,etc., and in particular, the vaginal suppository is useful forprevention of HIV infection.

As the pharmaceutically acceptable carrier, a variety of organic orinorganic carriers that are commonly used as materials forpharmaceutical preparation may be used, and they are added as anexcipient, a lubricant, a binder or a disintegrant in solidpreparations, and as a solvent, a solubilizing agent, a suspendingagent, an isotonic agent, a buffer, a soothing agent or the like inliquid preparations. Other additives for preparation such as anantiseptic agent, an antioxidant, a colorant, a sweetener or the likemay also be used, if necessary. Preferred examples of the excipientinclude lactose, sucrose, D-mannitol, starch, crystalline cellulose,light anhydrous silica and the like. Preferred examples of the lubricantinclude magnesium stearate, calcium stearate, talc, colloidal silica andthe like. Preferred examples of the binder include crystallinecellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.Preferred examples of the disintegrant include starch,carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcroscarmellose, sodium carboxymethylstarch and the like. Preferredexamples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil and the like. Preferred examplesof the solubilizing agent include polyethylene glycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate and the like.Preferred examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate, etc.; hydrophilic polymers such as polyvinyl alcohol,polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,etc.; and the like. Preferred examples of the isotonic agent includesodium chloride, glycerin, D-mannitol and the like. Preferred examplesof the buffer include buffer solutions of salts such as phosphate,acetate, carbonate, citrate and the like. Preferred examples of thesoothing agent include benzyl alcohol and the like. Preferred examplesof the antiseptic agent include para-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like. Peferred examples of the antioxidant includesulfite salts, ascorbic acid and the like.

The compound represented by the formula (I) of the present invention ora salt thereof has excellent CCR antagonistic action, in particular,CCR5 and/or CCR2 antagonistic action, and especially, strong CCR5antagonistic action, and therefore it can be used in prevention andtreatment of human HIV infection, for example, AIDS, and also inprevention and treatment of other various diseases. Further, thecompound represented by the formula (I) of the present invention or asalt thereof has low toxicity and can be used safely.

For example, the pharmaceutical composition containing the compoundrepresented by the formula (I) of the present invention or a saltthereof can be used as a CCR5 antagonist, for example, a prophylacticand/or therapeutic agent for AIDS and a suppressive agent for diseaseprogression of AIDS. Furthermore, the pharmaceutical compositioncontaining the compound represented by the formula (I) of the presentinvention or a salt thereof may be used as a prophylactic and/ortherapeutic agent for a variety of diseases, such as a prophylacticand/or therapeutic agent for graft versus host disease (GVHD) and/orrejection reaction, a prophylactic and/or therapeutic agent for chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, chronic nephritis orarteriosclerosis, and the like.

Examples of the diseases for which the prophylactic and/or therapeuticagent of the present invention is used, include graft rejection(post-transplantational rejection, post-transplantational polycythemia,hypertension, organ disorder, vascular hypertrophy, graft versus hostdisease, etc.); arthritic osteopathic diseases such asperiostitis/meningitis, etc. (chronic rheumatoid arthritis,osteoarthritis deformans, rheumatoid myelitis, osteoporosis, abnormalgrowth of cell, fracture, refracture, osteomalacia, osseous Behcet'sdisease, ankylosing myelitis, articular tissue destruction bygonarthritis deformans and diseases similar thereto, etc.); autoimmunediseases (collagen disease, SLE (systemic lupus erythematosus),pachyderms, polyarteritis, myasthenia gravis, multiple sclerosis, etc.);allergic diseases (allergic nasal catarrh, conjunctivitis,gastrointestinal allergy, pollinosis, anaphylaxis, atopic dermatitis,bronchial asthma, etc.); inflammatory enteropathic diseases (ulcerativecolitis, Crohn's disease, gastritis, gastric ulcer, gastric cancer,post-gastrotomic disorder, dyspepsia, esophageal ulcer, pancreatitis,polyp of the colon, cholelithiasis, hemorrhoids, peptic ulcer,situational ileitis, etc.); inflammatory diseases (retinopathy,post-operative and post-traumatic inflammation, remission of puffiness,pharyngitis, cystitis, meningitis, inflammatory ophthalmic diseases,etc.); respiratory diseases (cold syndrome, pneumonia, asthma, pulmonaryhypertension, pulmonary thrombi/pulmonary obliteration, pulmonarysarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis,adult tachypnea syndrome, chronic, obliterative pulmonary diseases,etc.); infectious diseases (viral infection caused by cytomegalovirus,influenza virus, herpes virus or the like, rickettsia infection,bacterial infection, sexually transmitted diseases, carinii pneumonia,helicobacter pylori infection, systemic fungal infection, tuberculosis,invasive staphylococcal infection, acute viral encephalitis, acutebacterial meningitis, AIDS encephalopathy, septicemia, sepsis, sepsisgravis, septic shock, endotoxin shock, toxic shock syndromes, etc.);cancers and accompanying cachexia, cancer metastases (bladder cancer,breast cancer, cervical cancer, ovarian cancer, chronic lymphoblasticleukemia, chronic myeloid leukemia, colon cancer, rectal cancer, coliccancer, multiple myeloma, malignant myeloma, prostatic cancer, lungcancer, gastric cancer, Hodgkin's disease, malignant melanoma, malignantlymphoma, etc.); non-Hodgkin's lymphoma; non-small cell lung cancer;malignant melanoma, neurodegenerative diseases (Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington'schorea, diabetic neural disorder, Creutzfeldt-Jakob disease, etc.);mental diseases (depression, epilepsia, alcoholism etc.); schizophrenia;venous dysfunction; central nerve disorder (disorder of intracerebralbleeding, brain infarction, etc. and aftereffect/complication therefrom,cephalic trauma, spinal damage, brain edema, sensory malfunction,sensory dysfunction, autonomic nervous malfunction, autonomic nervousdysfunction, and the like); central damage (cephalic trauma, spinaldamage, whiplash injury, etc.); vascular dementia (multiinfarctdementia, Binswanger's disease, etc.); cerebrovascular accident(asymptomatic cerebrovascular accident, transient cerebral ischemicattack, stroke, cerebrovascular dementia, hypertensive encephalopathy,etc.); recurrence and aftereffect of cerebrovascular accident (neuralsymptom, mental symptom, subjective symptom, operational disorder indaily life, etc.); cerebral vascular dementia; post-cerebrovascularobliteration central hypofunction; disorder or abnormality of cerebralcirculation and autoregulation of renal circulation; blood brain barrierdisorder; anxiety symptom; acute coronary artery syndromes includingunstable angina, etc.; anxious mental state; amnesia; prosopalgia;otolaryngological disease (Meniere's syndrome, tinnitus, gustationdisorder, dizziness, dysequilibrium, dysphagia, etc.); migraine; chronicpain; dermatoses (keloid, angioma, psoriasis, etc.); arteriosclerosisobliterans; thromboangiitis obliterans; peripheral obstruction;postischemic reperfusion injury; Raynaud's disease; Buerger's disease;myocarditis; cardiac ischemia; cardiac infarction; progress of cardiacfailure after cardiac infarction; cardiomyopathy; cardiac hypertrophy;acute cardiac failure and chronic (including estatic) cardiac failure;angina pectoris; arrhythmia; tachycardia; circadian rhythm disorder ofblood pressure; abnormality in characteristic of blood haemocytecomponents (enhancement in platelet aggregation, abnormality oferythrocyte deformability, enhancement in leucocyte adhesiveness,increase in blood viscosity, polycythemia, vascular peliosis, autoimmunehemolytic anemia, disseminated intravascular coagulation syndrome,multiple myelopathy, etc.); arteriosclerosis including atherosclerosis(aneurysm, coronary arteriosclerosis, cerebro arteriosclerosis,peripheral arteriosclerosis, etc.); vascular reocclusion and restenosisafter bypass operation; vascular hyperplasia or occlusion and organmalfunction after intervention (transdermal coronary arterioplasty,stent detention, coronary autoscope, vascular ultrasound therapy,coronary injection thrombolytic therapy, etc.); production andenhancement of vasoactive materials and thrombi inducing materials(endothelin, thromboxan A2, etc.); arterialization (including abnormalvasculogenesis in abnormal capillary vasoganglion formation in theatherosclerotic outer membrane); thrombosis; fat storage diseaseacceleration; ophthalmic diseases (glaucoma, ocular hypertensiondisease, etc.); hypertension; hypertensive tinnitus; dialysishypotension; endothelial cell and organ disorders; endocrinopathy(Addison's disease, Cushing's syndrome, melanocytoma, primaryaldosteronism, etc.); nephritis; renal diseases (nephritis,glomerulonephritis, glomerulosclerosis, renal failure, thromboticmicroangiopathy, dialysis complications, organ disorders includingnephropathy by radiation, diabetic nephropathy, etc.); diabetic diseases(insulin-dependent diabetes, diabetic complications, diabeticretinopathy, diabetic microangiopathy, diabetic neuropathy, etc.);glucose tolerance abnormality; hepatic diseases (hepatitis (includingchronic hepatitis), hepatic cirrhosis, etc.); interstitial hepaticdiseases; chronic pancreatitis; portal pressure enhancement; obesity;male sterility; gynecologic diseases (climacteric disorder, gestationaltoxicosis, endometriosis, hysteromyoma, ovarian disease, mammarydisease, etc.); edema; chronic fatigue syndromes; prostatomegaly;Behcet's disease; Hodgkin's disease; lacunar infarction; consciousnessdisorder; psoriasis; diseases due to environmental or occupationalfactors (disorder caused by radiation, disorders caused by ultravioletray/infrared ray/laser ray, altitude sickness, etc.); intermittentclaudication; and the like.

The pharmaceutical composition containing the compound represented bythe formula (I) or a salt thereof may vary depending on the kind ofdisease to be treated and may be used in combination with other drugs.Examples of the other drugs include HDL-increasing drugs [a squalenesynthase inhibitor, a CETP inhibitor, a LPL activator, etc.]; aprophylactic and/or therapeutic agent for HIV infection [nucleic acidreverse transcriptase inhibitors such as zidovudine, didanosine,zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovirdipivoxil, fozivudine tidoxil, etc., non-nucleic acid reversetranscriptase inhibitors such as nevirapine, delavirdine, efavirenz,loviride, immunocal, oltipraz, etc., protease inhibitors such assaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir,lasinavir, lopinavir, etc.]; NMG-CoA reductase inhibitors [cerivastatin,atorvastatin, pravastatin, simvastatin, itavastatin, lovastatin,fluvastatin,(+)-3R,5S-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino]pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoicacid, etc.]; atopic dermatitis drugs [sodium cromoglycate, etc.];allergic nasal catarrh drugs [sodium cromoglycate, chlorpheniraminemaleate, alimemazine tartrate, clemastine fumarate, homochlorcyclizinehydrochloride, terfenadine, mequitazine, etc.]; imipenem•cilastatinsodium; endotoxin antagonists or antibodies; oxidosqualene-lanosterolcyclase [e.g., decalin derivatives, azadecalin derivatives and indanederivatives]; calcium antagonists (diltiazem, etc.); glycerol;cholinesterase inhibitors (e.g., Aricept (donepezil), etc.); compoundssuppressing cholesterol uptake [e.g., sitosterol, neomycin, etc.];compounds inhibiting cholesterol biosyntheses [e.g., HMG-CoA reductaseinhibitors such as lovastatin, simvastatin, pravastatin, etc.];

cyclooxygenase inhibitors [Cox-I, Cox-II inhibitors such as celecoxib,rofecoxib, salicylic acid derivatives such as aspirin and the like,diclofenac, indometacin, loxoprofen, etc.]; signal transductioninhibitors, squalene epoxidase inhibitors [e.g., NB-598 and theanalogous compounds, etc.]; steroidal drugs [dexamethasone, hexestrol,methimazole, betamethasone, triamcinolone, triamcinolone acetonide,fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone,cortisone acetate, hydrocortisone, fluorometholone, beclomethasonepropionate, estriol, etc.]; diacerin; nicotinic acid and derivatives andanalogues thereof [e.g., acipimox and probucol]; nicergoline, nephroticsyndrome drugs: prednisolone (Predonine), prednisolone sodium succinate(Predonine), methylprednisolone sodium succinate (Solumedrol),betamethasone (Rinderon), dipyridamole (Persantine), dilazephydrochloride (Comelian), ticlopidine, clopidogrel, antiplatelet drugsand anticoagulants such as FXa inhibitors, etc.; barpital-basedanticonvulsants or anaesthetic drugs (phenobarbital, mephobarbital,metharbital, etc.); Parkinson's disease drugs (e.g., L-DOPA, etc.);histamine receptor blockers (cimetidine, famotidine, etc.);hydantoin-based anticonvulsant drugs (phenytoin, mephenytoin, ethotoin,etc.); piroxicam, fibrates [e.g., clofibrate, benzafibrate, gemfibrozil,etc.]; prostaglandins; megestrol acetate; gastric and intraduodenalulcer drugs: antacids [e.g., histamine H2 antagonists (cimetidine,etc.), proton pump inhibitors (lansoprazole, etc.), and the like];inflammatory mediator inhibitors; coronary vasodilators: nifedipine,diltiazem, nicoradil, nitrite drugs, etc.; infectious disease drugs:[e.g., antibiotic formulations (cefotiam hydrochloride, cefozopranhydrochloride, ampicillin, etc.), chemotherapeutic agents (sulfa drugs,synthetic antibacterial agents, antiviral agents, etc.), biologicformulations (vaccines, blood preparations including immunoglobulins)etc.] etc.; hepatic disease drugs: glycyrrhizin formulations [e.g.,Stronger Minophagen, etc.]; liver hydrolysate; SH compounds [e.g.,glutathione, etc.]; special amino acid formulations [e.g., aminoleban,etc.]; phospholipids [e.g., polyene-phosphatidylcholine, etc.]; vitamins[e.g., vitamin B₁, B₂, B₆, B₁₂, C, etc.]; adrenocortical hormones [e.g.,dexamethasone, betamethasone, etc.]; interferons [e.g., interferon α, β,etc.]; hepatic encephalopathy drugs [e.g., lactulose, etc.]; hemostaticagents used in cases of rupture of esophageal and gastric varices [e.g.,vasopressin, somatostatin, etc.] etc.; arthritis drugs; muscle relaxants[pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine, etc.]; vasodilators [oxyfedrine,diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa,guanabenz, etc.]; vasoconstrictors [dopamine, dobutamine, denopamine,etc.]; platelet coagulation inhibitors (ozagrel, etc.); thrombogenesisprophylactic and/or therapeutic drugs: anticoagulant drugs [e.g.,heparin sodium, heparin calcium, warfarin calcium (Warfarin), Xainhibitors]; thrombolytic drugs [e.g., tPA, urokinase]; antiplateletdrugs [e.g., aspirin, sulfinpyrazone (Anturan), dipyridamole(Persantine), ticlopidine (Panaldine), cilostazol (Pletal), GPIIb/IIIaantagonists (ReoPro)]; antidepressants [imipramine, clomipramine,noxiptiline, fenelzin, amitriptyline hydrochloride, nortriptylinehydrochloride, amoxapine, mianserin hydrochloride, maprotilinehydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride,etc.]; antiepileptic drugs [gabapentin, phenytoin, ethosuximide,acetazolamide, chlordiazepoxide, trimethadione, carbamazepine,phenobarbital, primidone, sultiame, sodium valproate, clonazepam,diazepam, nitrazepam, etc.]; antiallergic drugs [diphenhydramine,chlorpheniramine, tripelennamine, methodilamine, clemizole,diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast,repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine,azlastine, epinastine, ozagrel hydrochloride, pranlukast hydrate,seratrodast, fexofenadine, ebastine, bucillamine, oxatomide, StrongerNeo-Minophagen C, tranexamic acid, ketotifen fumarate, etc.];anticholinergic drugs (e.g., ipratropium bromide, flutropium bromide,oxitropium bromide, etc.); anti-Parkinson drugs (dopamine, levodopa,etc.); antirheumatic drugs; anti-inflammatory drugs (e.g., aspirin,acetaminophen, diclofenac sodium, ibuprofen, indometacin, loxoprofensodium, dexamethasone, etc.); anticoagulant and antiplatelet drugs[sodium citrate, activated protein C, tissue factor pathway inhibitors,antithrombin III, dalteparin sodium, argatroban, gabexate, ozagrelsodium, ethyl icosapentate, beraprost sodium, alprostadil,pentoxifylline, tisokinase, streptokinase, hebarin, etc.]; anticoagulanttherapeutic drugs [dipyridamole (Bersantine), dilazep hydrochloride(Comelian), ticlopidine, clopidogrel, Xa inhibitors]; antibacterialdrugs [(1) sulfa drugs [sulfamethizole, sulfisoxazole,sulfamonomethoxine, sulfamethizole, salazosulfapyridine, sulfadiazinesilver, etc.], (2)quinoline-based antibacterial drugs [nalidixic acid,pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin,tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacinhydrochloride, sparfloxacin, fleroxacin, etc.], (3) antituberculousdrugs [isoniazid, ethambutol (ethambutol hydrochloride),p-aminosalicylic acid (calcium p-aminosalicylate), pyrazinamide,ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycinsulfate, cycloserine, etc.], (4) anti-acid fast bacterial drugs[diaphenylsulfone, rifampicilin, etc.], (5) antiviral drugs[idoxuridine, acyclovir, vidarabine, ganciclovir, etc.], (6) anti-HIVdrugs [zidovudine, didanosine, zalcitabine, indinavir sulfateethanolate, ritonavir, etc.], (7) spirocheticide, (8) antibiotics[tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotiam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefmetazole, cefminox, cefoxitin,cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone,ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or saltsthereof, griseofulvin, lankacidins [J. Antibiotics, 38, 877-885 (1985)],etc.], cefixime, levofloxacin]; antithrombotic drugs (argatroban, etc.);antiprotozoal drugs [metronidazole, tinidazole, diethylcarbamazinecitrate, quinine hydrochloride, quinine sulfate, etc.]; antitumor drugs[6-O-(N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuplin acetate, buserelin acetate,etc.]; antifungal drugs [(1) polyethylene-based antibiotics (e.g.,amphotericin B, nystatin, trichomycin), (2) griseofulvin, pyrrolnitrin,etc., (3) cytosine metabolism antagonists (e.g., flucytosine), (4)imidazole derivatives (e.g., econazole, clotrimazole, miconazolenitrate, bifonazole and croconazole), (5) triazole derivatives (e.g.,fluconazole, itoraconazole, azole compounds[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl-3-(2H,4H)-1,2,4-triazolone],(6) thiocarbamate derivatives (e.g., trinaphthol], (7)echinocandin-based derivatives (e.g., caspofungin, FK-463,V-echinocandin), etc.]; antipsychotic drugs [chlorpromazinehydrochloride, prochlorperazine, trifluoperazine, thioridazinehydrochloride, perphenazine maleate, fluphenazine enanthate,prochlorperazine maleate, levomepromazine maleate, promethazinehydrochloride, haloperidol, bromperidol, spiperone, reserpine,clocapramine hydrochloride, sulpiride, zotepine, etc.]; antiulcer drugs[metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide,pirenzepine, cimetidine, ranitidine, famotidine, urogastron,oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate,gefarnate, aldioxa, teprenone, prostaglandins, etc.]; anti-diabeticdrugs [e.g., pioglitazone, nateglinide, voglibose, acarbose, etc.];antiobesity drugs (mazindol, etc.); antirheumatic drugs, etc.;antianxiety drugs [diazepam, lorazepam, oxazepam, chlordiazepoxide,medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam,fludiazepam, hydroxyzine, etc.]; antiarrhythmic drugs: disopyramide,lidocaine, quinidine sulfate, flecainide acetate, mexiletinehydrochloride, amiodarone hydrochloride, and β blockers, Ca antagonists,etc.; antiasthmatic drugs [isoprenaline hydrochloride, salbutamolsulfate, procaterol hydrochloride, terbutaline sulfate, trimetoxynolhydrochloride, tulobuterol hydrochloride, orciprenaline sulfate,fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide,oxitropium bromide, flutropium bromide, theophylline, aminophylline,sodium cromoglycate, tranilast, repirinast, amlexanox, ibudilast,ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrelhydrochloride, pranlukast hydrate, seratrodast, dexamethasone,prednisolone, hydrocortisone, beclomethasone propionate, fluticasonepropionate, beclomethasone propionate, procaterol, etc.];anti-hypothyroidism drugs [dried thyroid (Thyreoid), levothyroxinesodium (Thyradin S), liothyronine sodium (thyronine, tyronamine)];nephrotic syndrome drugs [prednisolone (Predonine), prednisolone sodiumsuccinate (Predonine), methylprednisolone sodium succinate (Solumedrol),betamethasone (Rinderon)]; antihypertensive drugs [(1) sympathetic nerveinhibitors [α2 stimulants (e.g., clonidine, guanabenz, guanfacine,methyldopa, etc.), ganglionic blockers (e.g., hexamethonium,trimethaphan, etc.), presynaptic blockers (e.g., ARSA-Oxylone,dimethylaminoreserpinate, rescinnamine, reserpine, syrosingopine, etc.),neuronal blockers (e.g., betanidine, guanethidine, etc.), α1 blockers(e.g., bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.), βblockers (e.g., propranolol, nadolol, timolol, nipradilol, bunitrolol,indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol,atenolol, pisoprolol, metoprolol, labetalol, amosulalol, arotinolol,etc.), and the like], (2) vasodilators [calcium channel antagonists(e.g., manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine,benidipine, amlodipine, aranidipine, etc.), phthalazine derivatives(e.g., budralazine, cadralazine, ecarazine, hydralazine, todralazine,etc.), and the like], (3) ACE inhibitors [alacepril, captopril,cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril,quinapril, imidapril, benazepril, perindopril, etc.)], (4) AIIantagonists [losartan, candesartan, valsartan, telmisartan, irbesartan,forasartan, etc.], (5) diuretic drugs (e.g., diuretic drugs describedabove, etc.); antihypertensive drugs: diuretic drugs [e.g., furosemide(Lasix), bumetanide (Lunetoron), azosemide (DIART)], antihypertensivedrugs [e.g., ACE inhibitors, (enalapril maleate (RENIVACE), etc.) and Caantagonists (manidipine, amlodipine, etc.), α or β receptor blockers,etc.], antihyperlipemia drugs [HMG-CoA reductase inhibitors (e.g.,fluvastatin, cerivastatin, atorvastatin, etc.), fibrates [e.g.,simfibrate, aluminum clofibrate, clinofibrate, fenofibrate, etc.], anionexchange resin (e.g., cholestyramine, etc.), nicotinic acid drugs (e.g.,nicomol, niceritrol, tocopherol nicotinate, etc.), polyvalentunsaturated fatty acid derivatives (e.g., ethyl icosapentate, polyenephosphatidylcholine, melinamide, etc.), phytosterols (e.g.,gamma-oryzanol, soy sterol, etc.), elastase, sodium dextran sulfate,squalene synthase inhibitors, CETP inhibitors, ethyl2-chloro-3[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chem. Pharm.Bull., 38, 2792-2796 (1990)], etc.]; osseous disease drugs: calciumformulations (e.g., calcium carbonate, etc.), calcitonin formulations,activated vitamin D₃ formulations (e.g., alfacalcidol (Alfarol, etc.),calcitriol (Rocaltrol), etc.), sex hormones (e.g., estrogen, estrandiol,etc.), hormone formulations [e.g., conjugated estrogen (Premarin),etc.], ibriflavone formulations [Osten, etc.], vitamin K₂, vitamin K₂formulations [e.g., menatetrenone (Glakay), etc.], bisphosphonate-basedformulations (etidronate, etc.), prostaglandin E2, fluorine compounds(e.g., sodium fluoride, etc.), bone morphogenetic protein (BMP),fibroblast growth factor (FGF), platelet derived growth factor (PDGF),transforming growth factor (TGF-β), insulin-like growth factor-1 and -2(IGF-1, -2), parathyroid adrenal hormones (PTH), and compounds describedin EP-A1-376197, EP-A1-460488, and EP-A1-719782 (e.g.,(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide,etc.), and the like, fat-soluble vitamin drugs [(1) vitamin A family:vitamin A₁, vitamin A₂, and retinol palmitate, (2) vitamin D family:vitamin D₁, D₂, D₃, D₄ and D₅, (3) vitamin E family: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate,(4) vitamin K family: vitamin K₁, K₂, K₃ and K₄, (5) folic acids(vitamin M, etc.); vitamin derivatives [various vitamin derivatives,e.g., vitamin D₃ derivatives such as 5,6-trans-cholecalciferol,2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, vitamin D₂derivatives such as 5,6-trans-ergocalciferol, and the like];disease-modifying antirheumatic and immunosuppressive drugs [e.g.,methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, oralgold drugs]; hypertensors [dopamine, dobutamine, denopamine, digitoxin,digoxin, methyldigoxin, lanatoside C, G-strophanthin, etc.]; myocardialprotective drugs: heart ATP—K opener, Na—H exchange inhibitors,endothelin antagonists, urotensin antagonist, etc., cardiac failuredrugs [cardiac stimulants (e.g., digitoxin, digoxin, methyldigoxin,lanatoside C, proscillaridin, etc.), α, β stimulants (e.g., epinephrine,norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine,denopamine, etc.), phosphodiesterase inhibitors (e.g., amrinone,milrinone, olprinone hydrochloride, etc.), calcium channel sensitivityenhancer (e.g., pimobentan, etc.), nitrate drugs (e.g., nitroglycerin,isosorbide nitrate, etc.), ACE inhibitors (e.g., the ACE inhibitordescribed above, etc.), diuretic drugs (e.g., diuretic drugs describedabove, etc.), calperitide, ubidecarenone, vesnarinone, aminophylline,etc.]; neurotrophic factors; renal failure and nephropathy drugs;biological formulations [e.g., monoclonal antibodies (e.g., anti-TNF-αantibodies, anti-IL-12 antibodies, anti-IL-6 antibodies, anti-ICAM—Iantibodies, anti-CD4 antibodies, etc.), soluble receptors (e.g., solubleTNF-α receptors, etc.), protein ligands (IL-I receptor antagonist,etc.)]; bile acid binding resins [e.g., cholestyramine, colestipol,etc.]; biliary tract disease drugs: cholepoietic drugs [e.g.,dehydrocholic acid, etc.], cholekinetic drugs [e.g., magnesium sulfate,etc.], and the like; central nervous system agonists: antianxiety drugs,hypnotic and sedative drugs, anesthetic drugs, spasmolytic drugs,autonomic drugs, anti-Parkinson drugs and other psychoneuro drugs, etc.;antitussive and expectorants [ephedrine hydrochloride, noscapinehydrochloride, codeine phosphate, dihydrocodeine phosphate,isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrinehydrochloride, alloclamide, clofedanol, picoperidamine, cloperastine,protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol,morphine hydrochloride, dextromethorphan hydrobromide, oxycodonehydrochloride, dimemorfan phosphate, tipepidine hibenzate, pentoxyverinecitrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteinehydrochloride, carbocisteine, etc.], sedative drugs [chlorpromazinehydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital,pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam,estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam,bromovaleryl urea, chloral hydrate, triclofos sodium, etc.], analgesicand antiphlogistic drugs [e.g., central analgesic drugs (e.g., morphine,codeine, pentazocine, etc.), steroidal drugs (e.g., prednisolone,dexamethasone, betamethasone, etc.), antiphlogistic enzymatic drugs(e.g., bromelain, lysozymes, proctase, etc.)], diabetic drugs[sulfonylurea drugs (e.g., tolbutamide, chlorpropamide, glyclopyramide,acetohexamide, tolazamide, glibenclamide, glibuzole, etc.), biguanidedrugs (e.g., metformin hydrochloride, buformin hydrochloride, etc.)

α-glucosidase inhibitors (e.g., voglibose, acarbose, etc.), insulinresistance improvers (e.g., pioglitazone, troglitazone, etc.), insulin,glucagon, diabetic complication drugs (e.g., epalrestat, thioctic acid,etc.), actos, rosiglitazone, kinedak, penfill, humulin, euglucon,glimicron, daonil, novolin, monotard, insulin family, glucobay, dimelin,rastinone, bacilcon, deamelin S, Iszilinacid, etc.]; brain functionactivating agents (e.g., idebenone, vinpocetine, etc.); urinary and malegenital disease drugs [e.g., prostatomegaly drugs (tamsulosinhydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.),prostate cancer drugs (leuprorelin acetate, goserelin acetate,chlormadinone acetate, etc.)], etc; nonsteroidal antiinflammatory drugs[acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine,migrenin, aspirin, mefenamic acid, fulfenamic acid, diclofenac sodium,loxoprofen sodium, phenylbutazone, indometacin, ibuprofen, ketoprofen,naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine,epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate,camostat mesilate, urinastatin, colchicine, probenecid, sulfinpyrazone,benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate,sodium salicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone or salts thereof, etc.]; frequent urination and incontinencedrugs [flavoxate hydrochloride, etc.]; unstable plaque stabilizers [MMPinhibitors, chymase inhibitors, etc.]; arrhythmic drugs [sodium channelblockers (e.g., quinidine, procainamide, disopyramide, ajmaline,cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone,flecainide, pilsicainide, phenytoin, etc.), β blockers (e.g.,propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol,metoprolol, pisoprolol, pindolol, carteolol, arotinolol, etc.),potassium channel blockers (e.g., amiodarone, etc.), calcium channelblockers (e.g., verapamil, diltiazem, etc.), and the like]; gynecologicdisease drugs [e.g., climacteric disorder drugs (conjugated estrogen,estradiol, testosterone enanthate, estradiol valerate, etc.), breastcancer drugs (tamoxifen citrate, etc.), endometriosis and hysteromyomadrugs (leuprorelin acetate, danazol, etc.)], etc.; anesthetic drugs [a.local anaesthetic drugs [cocaine hydrochloride, procaine hydrochloride,lidocaine, dibucaine hydrochloride, tetracaine hydrochloride,mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocainehydrochloride, ethyl aminobenzoate, oxethazaine], etc.]; b. systemicanesthetic drugs [(1) inhalation anesthetic drugs (e.g., ether,halothane, nitrous oxide, influrane, enflurane), (2) intravenousanesthetic drugs (e.g., ketamine hydrochloride, droperidol, thiopentalsodium, thiamylal sodium, pentobarbital), etc.]]; anesthetic antagonists[levallorphan, nalorphine, naloxone, or salts thereof, etc.]; chroniccardiac failure drugs: cardiac stimulants [e.g., cardiac glycoside(digoxin), etc., β receptor stimulants (catecholamine preparations suchas denopamine, dobutamine), PDE inhibitors, etc.]; diuretic drugs [e.g.,furosemide (Lasix), spironolactone (Aldactone), bumetanide (Lunetoron),azosemide (Diart), etc.]; ACE inhibitors [e.g., enalapril maleate(Renivace), etc.]; Ca antagonists [e.g., amlodipine, manidipine, etc.]and β receptor blockers, etc.; immunomodulators [cyclosporin,tacrolimus, gusperimus, azathioprine, antilymphocyte sera, driedsulfonated immunoglobulins, erythropoietins, growth promotingglycoproteins, interleukins, interferons, etc.]; diuretic drugs[thiazide-based diuretic drugs (benzylhydrochlorothiazide,cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide,methyclothiazide, penfluthiazide, polythiazide, trichlormethiazide,etc.), loop diuretic drugs (chlortalidone, clofenamide, indapamide,mefruside, meticrane, sotrazone, tribamide, quinethazone, metolazone,furosemide, mefruside, etc.), potassium-sparing diuretic drugs(spironolactone, triamterene, etc.)]; erectile dysfunction drugs(Viagra, apomorphine, etc.); and the like.

These drugs may be formulated, separately or simultaneously, by mixingwith pharmaceutically acceptable carriers, excipients, binders, diluentsor the like, and can be administered either orally or parenterally. Whenthe drugs are formulated separately, the separately preparedformulations may be mixed using a diluent or the like at the time of useand then administered, or each of the separately prepared formulationsmay be administered, simultaneously or separately with a time interval,to the same subject. Kit products that are to be used for mixing theseparately prepared formulations using a diluent or the like at the timeof use and administering (for example, an injection kit includingampoules for containing individual powdery drug, and a diluent formixing and dissolving two or more drugs at the time of use, and thelike), kit products that are to be used for administering each of theseparately prepared formulations, simultaneously or separately with atime interval, to the same subject (for example, a tablet kit foradministering two or more tablets, simultaneously or separately with atime interval, each tablet containing each of the drugs and placed inthe same or separate bags, with space for memorandum provided, ifnecessary, on the bags for indication of the drug administration time,or the like), and the like are also included to the pharmaceuticalcomposition of the present invention.

Dosage of the pharmaceutical composition of the present invention can beappropriately selected by taking into consideration of the subject to beadministered, age and body weight of the subject, symptoms,administration time, administration route, dosage form and the like.

The dosage of a particular subject can be determined according to thesubject's age, body weight, general health condition, gender, meal,administration time, administration route, excretion rate and the extentof disease condition of the patient at the time of treatment, by takinginto consideration of these and other factors.

When the pharmaceutical composition described above is used as aprophylactic and therapeutic agent for AIDS and as a suppressive agentfor disease progression of AIDS, the dosage may vary depending on thepatient's condition, body weight or the method of administration.However, in the case of oral administration, the daily dosage is in arange of about 5 to 1000 mg, preferably about 10 to 600 mg, morepreferably about 10 to 300 mg, and particularly preferably about 15 to150 mg, as the active ingredient [i.e. as the compound of the formula(I)], for an adult having a body weight of 50 kg, and the composition isadministered once, or in 2 or 3 divided doses a day.

When the pharmaceutical composition described above is used as aprophylactic and therapeutic agent for graft versus host disease and/orrejection associated with transplantation of organ such as heart,kidney, liver, bone marrow or the like, administration of thecomposition starts three days before the transplantation and iscontinued even after the transplantation. The daily dosage of thepharmaceutical composition of the present invention may vary dependingon the patient's condition, body weight or method of administration, butin the case of oral administration, it is about 5 to 1000 mg, preferablyabout 10 to 600 mg, more preferably about 10 to 300 mg, and particularlypreferably about 15 to 150 mg, as the active ingredient [i.e., as thecompound represented by the formula (I)], for an adult having a bodyweight of 50 kg, and the composition is administered once, or in 2 or 3divided doses a day. In this case, the composition may also be used incombination with other suppressive agents for graft versus host diseaseand/or rejection associated with organ transplantation. Specificexamples of the suppressive agent for graft versus host disease and/orrejection associated with organ transplantation, which are used incombination with the compound represented by the above formula (I) or asalt thereof, include cyclosporin, tacrolimus, rapamycin, steroids,azathioprine, mycophenolate mofetil, mizoribine, etc. In the case ofusing these drugs in combination, if one of the drugs interferes withmetabolism of other drugs, the dosage of each drug is to beappropriately adjusted, but in general, the dosage for administration ofa single drug is employed for each of the drugs.

When the compound represented by the formula (I) described above or asalt thereof is used for diseases other than the suppressive agents forgraft versus host disease and/or rejection associated with organtransplantation, the daily dosage thereof may vary depending on the kindof the disease to be treated, the patient's condition, body weight, ormethod of administration. But, in the case of oral administration, thedosage is about 5 to 1000 mg, preferably about 10 to 600 mg, morepreferably about 10 to 300 mg, and particularly preferably about 15 to150 mg, as the active ingredient [i.e., as the compound represented bythe formula (I)], for an adult having a body weight of 50 kg, and thecomposition is administered once, or in 2 or 3 divided doses a day. Whenthe compound is used in combination with other drugs, the dosage of theother drugs is appropriately selected in a range of, for example, about1/200 to ½ or more and about 2 to 3 times or less of a general dosage.Further, in the case of using the compound in combination with two ormore drugs, if one of the drugs interferes with metabolism of the otherdrugs, the dosage of each drug is to be appropriately adjusted, but ingeneral, the dosage for administration of a single drug is employed foreach of the drugs.

Furthermore, the compound represented by the formula (I) or a saltthereof can be also included in or used in combination with blood fortransfusion or blood derivatives. Blood for transfusion or bloodderivatives are usually produced by mixing blood obtained from aplurality of persons, and in some cases, cells infected by HIV virus maybe co-present with HIV-uninfected cells. In such a case, there is fearfor infection of the uninfected cells. Thus, when the compoundrepresented by the formula (I) of the present invention is added toblood for transfusion or a blood derivative, it is possible to preventor control infection and proliferation of the virus. Especially, uponstorage of blood derivatives, addition of the compound represented bythe formula (I) of the present invention is effective for prevention orcontrol of infection and proliferation of the virus. In addition, whenblood for transfusion or a blood derivative contaminated with HIV virusis administered to a person, infection and proliferation of the HIVvirus in the body of the person administered with blood for transfusionor a blood derivative can be prevented by the compound represented bythe formula (I) that has been added to the blood for transfusion orblood derivative. For example, in the case of orally administering thecompound to an adult (body weight of about 60 kg) for preventing HIVinfection upon blood transfusion and use of blood derivatives, thedosage for a single administration is usually in a range of about 0.02to 50 mg/kg, preferably 0.05 to 30 mg/kg, and more preferably 0.1 to 10mg/kg, as the CCR antagonist, and the compound is preferablyadministered in about 1 to about 3 doses a day. As a matter of fact, therange of dosage can be adjusted on the basis of the unit dosagenecessary for dividing the daily dosage; however, as described above,the dosage can be determined by taking into consideration of the natureand severity of the disease, the patient's age, the body weight, thegeneral health condition, the gender, the meal, the administration time,the method of administration, the excretion rate and other factors. Inthis case, the method of administration can be also appropriatelyselected, and the above-described prophylactic agent for HIV infectionof the present invention may be added directly to the blood or bloodderivative to be transfused, prior to blood transfusion or use of bloodderivative. In such a case, the addition of the compound is preferablycarried out immediately before to 24 hours before, preferablyimmediately before to 12 hours before, and more preferably immediatelybefore to 6 hours before, the transfusion or use of blood derivative.

When the prophylactic agent for HIV infection of the present inventionis further administered in addition to the blood or blood derivative tobe transfused, at the time of blood transfusion or use of bloodderivative, the agent is preferably administered from 1 hour before tosimultaneously with transfusion or use of blood derivative, and morepreferably, the agent is administered 1 to 3 times per day, continuouslyfor 4 weeks.

Moreover, when the compound represented by the formula (I) or a saltthereof is used in combination with a reverse transcriptase inhibitorand/or a protease inhibitor, the dosage of the reverse transcriptaseinhibitor or the protease inhibitor is properly selected in a range ofabout 1/200 to ½ or more, to about 2 to 3 times or less of the usualdosage.

The usual dosages of the representative reverse transcriptase inhibitorsand protease inhibitors are as follows:

zidovudine: 100 mg

didanosine: 125 to 200 mg

zalcitabine: 0.75 mg

lamivudine: 150 mg

stavudine: 30 to 40 mg

saquinavir: 600 mg

ritonavir: 600 mg

indinavir: 800 mg

nelfinavir: 750 mg

A typical embodiment of combined use of the compound of the formula (I)or a salt thereof, and a reverse transcriptase and/or a proteaseinhibitor will be described below.

(1) About 10 to 300 mg of the compound of the formula (I) or the saltthereof and about 50 to 200 mg of zidovudine, per an adult of bodyweight of 50 kg, are administered in combination to the same object.Each medicine may be administered simultaneously or separately in a timeinterval of less than 12 hours.

(2) About 10 to 300 mg of the compound of the formula (I) or the saltthereof and about 300 to 1200 mg of saquinavir, per an adult of bodyweight of 50 kg, are administered in combination to the same object.Each medicine may be administered simultaneously or separately in a timeinterval of less than 12 hours.

The following Examples, Reference Examples, Experimental Example andFormulation Examples further illustrate the present invention in detailbut are not to be construed to limit the scope thereof.

EXAMPLE 1 Preparation of Compound 1

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (479 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.44 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.44 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure-to give(S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to asolution of3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylicacid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, andthen oxalyl chloride (0.063 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere,and then the resulting solution was added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.16 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirredovernight. Then, water was added and the mixture was extracted withethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the residue wasseparated and purified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=3:100) to give(S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide(294 mg) (Compound 1) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90-0.96 (12H, m), 1.33-1.46 (2H, m),1.50-1.76 (6H, m), 2.20-2.35 (1H, m), 2.58-2.67 (2H, m), 3.30-3.50 (2H,m), 3.55 (2H, t, J=6.9 Hz), 3.58-3.63 (2H, m), 3.76-3.82 (4H, m), 4.00(1H, d, J=11.7 Hz), 4.09-4.17 (3H, m), 6.54 (1H, s), 6.97 (2H, d, J=9.0Hz), 7.34 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=9.0 Hz), 7.42-7.44 (2H, m),7.55 (1H, s), 7.75 (2H, d, J=8.4 Hz), 8.15 (1H, s), 8.30 (1H, d, J=2.7Hz).

Elementary analysis: C₄₀H₅₁N₅O₄S.0.5H₂O, Calcd. C, 67.96; H, 7.41; N,9.91; Found. C, 68.08; H, 7.29; N, 9.72.

[α]_(D)=−131.7° (C=0.381% in ethanol)

EXAMPLE 2 Preparation of Compound 2

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (495 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.52 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.52 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to asolution of3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylicacid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, andthen oxalyl chloride (0.065 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere,and then the resulting solution was added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (1.2ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. Themixture was returned to room temperature and stirred overnight. Then,water was added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water twice and saturated brine once, andthen dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the residue was separated and purified bybasic silica gel column chromatography (ethyl acetate→methanol:ethylacetate=3:100) to give(S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide(310 mg) (Compound 2) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.87-0.99 (9H, m), 1.33-1.46 (2H, m),1.56-1.75 (8H, m), 2.60-2.70 (2H, m), 3.35-3.70 (6H, m), 3.76-3.82 (4H,m), 4.01 (1H, d, J=14.1 Hz), 4.09-4.17 (3H, m), 6.53 (1H, s), 6.97 (2H,d, J=9.0 Hz), 7.35-7.52 (7H, m), 7.75 (2H, d, J=9.0 Hz), 8.24 (1H, s),8.32 (1H, d, J=2.4 Hz).

Elementary analysis: C₃₉H₄₉N₅O₄S.0.5H₂O, Calcd. C, 67.60; H, 7.27; N,10.11; Found. C, 67.67; H, 7.22; N, 9.92.

[α]_(D)=−133.4° (C=0.321% in ethanol).

EXAMPLE 3 Preparation of Compound 3

(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (494 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.52 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.52 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. Then, to asolution of3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylicacid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, andthen oxalyl chloride (0.065 ml) was added at 0° C. The mixture wasreturned to room temperature and stirred for 30 minutes under a nitrogenatmosphere, and then the resulting solution was added dropwise to asolution of (S)-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilineand pyridine (1.2 ml) in tetrahydrofuran (10 ml) at 0° C. under anitrogen atmosphere. The mixture was returned to room temperature andstirred overnight. Then, water was added and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resultant wasseparated and purified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:20) to give(S)-3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline]-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxamide(199 mg) (Compound 3) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.88-0.97 (12H, m), 1.33-1.46 (2H, m),1.56-1.76 (4H, m), 2.10-2.20 (1H, m), 2.90-3.00 (2H, m), 3.49-3.58 (4H,m), 3.62 (2H, d, J=7.5 Hz), 3.77-3.83 (4H, m), 4.01 (1H, d, J=14.1 Hz),4.08-4.18 (3H, m), 6.54 (1H, s) 7.00 (2H, d, J=8.7 Hz), 7.30-7.36 (3H,m), 7.43-7.46 (3H, m) 7.69 (1H, d, J=2.4 Hz), 7.74 (2H, d, J=8.7 Hz),7.91 (1H, s) 8.34 (1H, d, J=2.4 Hz).

Elementary analysis: C₃₉H₄₉N₅O₄S.0.5H₂O, Calcd. C, 67.60; H, 7.27; N,10.10; Found. C, 67.50; H, 7.22; N, 9.97.

[α]_(D)=−133.1° (C=0.251% in ethanol)

EXAMPLE 4 Preparation of Compound 4

To a solution of3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylicacid (130 mg) in dichloromethane (10 ml) were added a drop of DMF. Then,oxalyl chloride (0.034 ml) was added thereto, and the mixture wasstirred for 1 hour under a nitrogen atmosphere. The resulting solutionwas added dropwise to a solution of4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (85 mg) inpyridine (10 ml) at 0° C. under a nitrogen atmosphere. The resultingmixture was stirred at room temperature under a nitrogen atmosphereovernight. Then, water was added and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure, and then the resulting residue was purified bybasic silica gel column chromatography (methanol:ethyl acetate=1:8) togive3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxamide(167 mg) (Compound 4) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91-0.97 (9H, m), 1.33-1.50 (2H, m),1.55-1.80 (6H, m), 2.05-2.25 (4H, m), 2.60-2.70 (1H, m), 2.90-3.00 (2H,m), 3.33-3.45 (2H, m), 3.49-3.63 (8H, m), 3.81 (2H, t, J=5.1 Hz),4.00-4.10 (2H, m), 4.16 (2H, t, 5.1 Hz), 7.00 (2H, d, 8.4 Hz), 7.26-7.32(3H, m), 7.43-7.54 (5H, m), 7.69 (1H, d, 2.1 Hz), 8.33 (1H, d, J=2.1Hz).

Elementary analysis: C₃₉H₅₂N₄O₄.0.25H₂O, Calcd. C, 72.58; H, 8.20; N,8.68; Found. C, 72.48; H, 8.47; N, 8.44.

REFERENCE EXAMPLE 1

To N-isobutyl-2-piperidone (1.13 g) was added an aqueous methanesulfonicacid solution (2.8 g/3.8 ml), and the mixture was refluxed at 120° C.for 2 days. The mixture was returned to room temperature, and sodiumcarbonate (1.55 g) was slowly added thereto. Then, the resultingsolution was added dropwise to a suspension of5-bromo-2-chloronicotinaldehyde (1.0 g) and sodium carbonate (1.25 g) inDMSO (10 ml) at 90° C. After stirring as it is for 2 hours, the mixturewas cooled to 0° C. and water was added thereto. Then, 1 N hydrochloricacid (20 ml) was added and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue as it is was dissolved in DMF (20 ml). Then, potassiumcarbonate (1.25 g) and iodomethane (0.57 ml) were added thereto, and themixture was stirred at room temperature under a nitrogen atmosphere for2 hours. Water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1→hexane:ethylacetate=4:1) to give methyl5-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]pentanoate (867 mg) asa yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.82 (6H, d, J=6.6 Hz), 1.50-1.70 (4H, m),1.92-2.05 (1H, m), 2.29 (2H, t, J=6.9 Hz), 3.28 (2H, d, J=7.5 Hz), 3.46(2H, t, J=7.2 Hz), 3.65 (3H, s), 8.00 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 9.88 (1H, s).

REFERENCE EXAMPLE 2

To a solution of methyl5-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]pentanoate (840 mg) indimethyl carbonate (20 ml) was added a 28% sodium methoxide solution inmethanol (874 mg), and the mixture was heated at 65° C. for 3 hoursunder a nitrogen atmosphere. The mixture was returned to roomtemperature, water was added, and then the resulting mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue waspurified by silica gel column chromatography (hexane:ethyl acetate=9:1)to obtain the residue, and then the obtained residue was washed withhexane-ethyl acetate to give methyl3-bromo-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(741 mg) as yellow crystals.

m.p. 79.5-80.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (6H, d, J=6.9 Hz), 1.30-1.50 (2H, m),2.16-2.25 (1H, m), 2.45-2.65 (2H, m), 3.20-3.55 (4H, m), 3.78 (3H, s),7.38 (1H, d, J=2.4 Hz), 7.62 (1H, s), 8.02 (1H, d, J=2.4 Hz).

Elementary analysis: C₁₆H₂₁N₂O₂Br, Calcd. C, 54.40; H, 5.99; N, 7.93;Found. C, 54.30; H, 6.00; N, 7.73.

REFERENCE EXAMPLE 3

A suspension of methyl3-bromo-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(690 mg), 4-(2-butoxyethoxy)phenylboric acid (605 mg) and potassiumcarbonate (702 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred under an argon atmosphere for 30 minutes.Tetrakis(triphenylphosphine)palladium (113 mg) was added thereto, andthe mixture was heated at 115° C. for 5 hours under an argon atmosphere.The solution was allowed to cool. Water was added and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=19:1→hexane:ethyl acetate=4:1) to give methyl3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(723 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.91-0.95 (9H, m), 1.33-1.66 (6H, m),2.23-2.32 (1H, m), 2.50-2.65 (2H, m), 3.35-3.45 (2H, m), 3.50-3.57 (4H,m), 3.78-3.81 (5H, m), 4.15 (2H, t, J=4.8 Hz), 6.97 (2H, d, J=8.7 Hz),7.41 (2H, d, J=8.7 Hz), 7.50 (1H, d, J=2.4 Hz), 7.82 (1H, s), 8.29 (1H,d, J=2.4 Hz).

REFERENCE EXAMPLE 4

To a solution of methyl3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(700 mg) in THF (24 ml) and methanol (24 ml) was added a 1 N aqueoussodium hydroxide solution (6 ml), and the mixture was heated at 90° C.for 3 hours. After cooling to 0° C., water was added thereto, and themixture was neutralized with 1 N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was washed with hexane togive3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(634 mg) as yellow crystals.

m.p. 135.0-136.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.88-0.95 (9H, m), 1.33-1.66 (6H, m),2.20-2.38 (1H, m), 2.55-2.65 (2H, m), 3.30-3.45 (6H, m), 3.80 (2H, t,J=4.8 Hz), 4.15 (2H, t, J=4.8 Hz), 6.98 (2H, d, J=8.7 Hz), 7.42 (2H, d,J=8.7 Hz), 7.52 (1H, d, J=2.4 Hz), 7.94 (1H, s), 8.31 (1H, d, J=2.4 Hz).

Elementary analysis: C₂₇H₃₆N₂O₄, Calcd. C, 71.65; H, 8.02; N, 6.19;Found. C, 71.87; H, 8.17; N, 6.13.

REFERENCE EXAMPLE 5

To N-propyl-2-piperidone (1.92 g) was added a 4 N aqueous sodiumhydroxide solution (6.8 ml), and the mixture was refluxed at 115° C. for5 hours. Thereto was added concentrated hydrochloric acid (2.27 ml) at0° C. to neutralize the resulting mixture. Then, sodium carbonate (2.88g), water (11.5 ml) and DMSO (18.2 ml) were added thereto. After themixture was heated to 90° C., a solution of5-bromo-2-chloronicotinaldehyde (1.5 g) in DMSO (23 ml) was addeddropwise thereto and the mixture was stirred as it is for 2 hours. Aftercooling to 0° C., water was added thereto. 6 N Hydrochloric acid (9 ml)was then added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure and theresidue as it is was dissolved in DMF (50 ml), and then potassiumcarbonate (2.31 g) and iodomethane (1.04 ml) were added thereto. Themixture was stirred at room temperature under a nitrogen atmosphere for2 hours. Water was added thereto and the mixture was then extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:1→hexane:ethylacetate=4:1) to give methyl5-[(5-bromo-3-formylpyridin-2-yl)(propyl)amino]pentanoate (909 mg) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.86 (3H, t, J=7.2 Hz), 1.60-1.69 (6H, m),2.32 (2H, t, J=6.9 Hz), 3.34-3.39 (2H, m), 3.46 (2H, t, J=6.9 Hz), 3.66(3H, s), 8.03 (1H, d, J=2.7 Hz), 8.31 (1H, d, J=2.7 Hz), 9.88 (1H, s).

REFERENCE EXAMPLE 6

To a solution of methyl5-[(5-bromo-3-formylpyridin-2-yl)(propyl)amino]pentanoate (880 mg) indimethyl carbonate (20 ml) was added a 28% sodium methoxide solution inmethanol (951 mg), and the mixture was heated at 65° C. for 6 hoursunder a nitrogen atmosphere. The mixture was returned to roomtemperature, water was added thereto, and then the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=9:1) to give methyl3-bromo-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(835 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.5 Hz), 1.40-1.70 (4H, m),2.40-2.65 (2H, m), 3.30-3.60 (4H, m), 3.78 (3H, s), 7.40 (1H, d, J=2.7Hz), 7.61 (1H, s), 8.06 (1H, d, J=2.7 Hz).

REFERENCE EXAMPLE 7

A suspension of methyl3-bromo-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(820 mg), 4-(2-butoxyethoxy)phenylboric acid (748 mg) and potassiumcarbonate (868 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred under an argon atmosphere for 30 minutes.Tetrakis(triphenylphosphine)palladium (140 mg) was added thereto, andthe mixture was heated at 115° C. for 6 hours under an argon atmosphere,which was allowed to cool. Water was added and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=4:1) to give methyl3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(870 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.91-0.98 (6H, m), 1.33-1.73 (8H, m),2.50-2.70 (2H, m), 3.35-3.60 (6H, m), 3.78-3.82 (5H, m), 4.15 (2H, t,J=4.8 Hz), 6.97 (2H, d, J=8.7 Hz), 7.41 (2H, d, J=8.7 Hz), 7.51 (1H, d,J=2.7 Hz), 7.79 (1H, s), 8.31 (1H, d, J=2.7 Hz).

REFERENCE EXAMPLE 8

To a solution of methyl3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate(850 mg) in THF (30 ml) and methanol (30 ml) was added a 1 N aqueoussodium hydroxide solution (7.5 ml), and the mixture was heated at 90° C.for 3 hours. After cooling to 0° C., water was added thereto, and themixture was neutralized with 1 N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was washed with hexane togive3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylicacid (739 mg) as yellow crystals.

m.p. 123.0-125.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.90-0.99 (6H, m), 1.33-1.73 (8H, m),2.55-2.65 (2H, m), 3.35-3.60 (6H, m), 3.80 (2H, t, J=5.1 Hz), 4.15 (2H,t, J=5.1 Hz), 6.98 (2H, d, J=8.7 Hz), 7.41 (2H, d, J=8.7 Hz), 7.52 (1H,d, J=2.4 Hz), 7.91 (1H, s), 8.33 (1H, d, J=2.4 Hz).

Elementary analysis: C₂₆H₃₄N₂O₄, Calcd. C, 71.21; H, 7.81; N, 6.39;Found. C, 71.17; H, 7.90; N, 6.10.

REFERENCE EXAMPLE 9

A mixture of potassium thiocyanate (119.2 g), dihydroxyacetone dimer(73.9 g) and propylamine hydrochloride (100 g) was portionwise added toa mixed solution of acetic acid (89 ml) and 1-butanol (590 ml). Themixture was stirred at room temperature for 1 day, and then water (118ml) was added thereto, followed by stirring for 30 minutes. Theprecipitated solid was collected by filtration, and further washed withwater (180 ml) twice and hexane once. The resulting solid was driedunder reduced pressure to give5-hydroxymethyl-2-mercapto-1-propylimidazole (71.2 g) as colorlesscrystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.87 (3H, t, J=7.4 Hz), 1.61-1.79 (2H, m),3.91 (2H, t, J=7.4 Hz), 4.32 (2H, s), 5.26 (1H, br), 6.79 (1H, s), 11.95(1H, s).

Elementary analysis: C₇H₁₂N₂OS.0.25H₂O, Calcd. C, 47.57; H, 7.13; N,15.85; Found. C, 47.22; H, 6.94; N, 15.99.

REFERENCE EXAMPLE 10

To 5.0 M nitric acid (370 ml) was added sodium nitrite (1.14 g), andthen 5-hydroxymethyl-2-mercapto-1-propylimidazole (71.0 g) wasportionwise added at 0° C. The mixture was returned to room temperatureand stirred for 2 hours, followed by adding water (200 ml). Thereto wasadded potassium carbonate at 0° C. to neutralize the mixture. Then, thesolvent was distilled off under reduced pressure. Ethanol was addedthereto, insolubles were filtered off, and the solvent was thendistilled off under reduced pressure. To the resulting residue was addedmethanol-ethyl acetate, and then basic silica gel was added thereto. Theresulting mixture was purified by basic silica gel column chromatography(methanol-ethyl acetate=1:8). The resulting solid was recrystallizedfrom diisopropyl ether-ethyl acetate to give5-hydroxymethyl-1-propylimidazole (33.6 g) as brown crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.96 (3H, t, J=7.4 Hz), 1.76-1.94 (2H, m),3.97 (2H, t, J=7.2 Hz), 4.63 (2H, s), 6.97 (1H, s), 7.48 (1H, s).

REFERENCE EXAMPLE 11

To 5-hydroxymethyl-1-propylimidazole (33.0 g) was portionwise addedthionyl chloride (80 ml) at 0C, and the mixture was heated at 90° C. for30 minutes under a nitrogen atmosphere. The mixture was returned to roomtemperature, and then the solvent was distilled off under reducedpressure. The resulting residue was dissolved in methanol, and thesolvent was again distilled off under reduced pressure. The resultingsolid was recrystallized from ethyl acetate to give5-chloromethyl-1-propylimidazole hydrochloride (43.8 g) as colorlesscrystals.

¹H-NMR (200 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.4 Hz), 1.84-1.95 (2H, m),4.18 (2H, t, J=7.2 Hz), 5.04 (2H, s), 7.82 (1H, s), 9.24 (1H, s).

REFERENCE EXAMPLE 12

4-Aminothiophenol (2.5 g) was dissolved in water (2.5 ml) andisopropanol (10 ml). Triethylamine (5.5 ml) was added thereto, and thenthe mixture was cooled to −15 to −10° C. A solution of5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g) in water(2.5 ml) was added dropwise thereto at −15 to −10° C., and the mixturewas stirred at the same temperature for 1 hour. After isopropanol wasdistilled off under reduced pressure, methyl isobutyl ketone (25 ml) wasthen added, and the organic layer was washed with water. To the organiclayer was added activated carbon (0.1 g), and the mixture was stirred atroom temperature for 10 minutes. The organic layer was concentrated anddissolved in methyl isobutyl ketone (30 ml). Separately,di-p-toluoyl-(D)-tartaric acid (7.7 g) was dissolved in a mixed solutionof toluene (90 ml) and methyl isobutyl ketone (60 ml), and to thesolution was added water (3.6 ml). Then, the above methyl isobutylketone solution was slowly added dropwise over 2 hours. After stirringthe resulting mixture for 1 hour, 30% hydrogen peroxide solution (6.8 g)was added thereto, and the mixture was stirred at room temperature for24 hours. Methanol (30 ml) was added thereto and the mixture was stirredat 50° C. for 8 hours. Water (30 ml) was added thereto, and the mixturewas stirred at room temperature for 5 hours. The precipitated crystalswere collected by filtration and washed with water (30 ml) to give(−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylaminedi-p-toluoyl-D-tartrate monohydrate (7.1 g).

m.p. 134-136° C.

REFERENCE EXAMPLE 13

To N-isobutyl-2-pyrrolidone (1.28 g) was added an aqueousmethanesulfonic acid solution (3.5 g/4.7 ml), and the mixture wasrefluxed at 130° C. for 3 days. The mixture was returned to roomtemperature, and sodium carbonate (1.92 g) was slowly added thereto. Theresulting solution was added dropwise at 90° C. to a suspension of5-bromo-2-chloronicotinaldehyde (1.0 g) and sodium carbonate (1.56 g) inDMSO (13 ml), and the mixture as it is was stirred for 4 hours, followedby cooling to 0° C. Water was added thereto, 6 N hydrochloric acid (5ml) was then added, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, and driedover magnesium sulfate. The solvent was distilled off under reducedpressure and the residue as it is was dissolved in DMF (20 ml).Potassium carbonate (1.25 g) and iodomethane (0.57 ml) were addedthereto, and the mixture was stirred at room temperature under anitrogen atmosphere for 2 hours. Water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=12:1→hexane:ethyl acetate=4:1) to give methyl4-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]butanote (763 mg) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.82 (6H, d, J=6.6 Hz), 1.88-2.04 (3H, m),2.27 (2H, t, J=7.2 Hz), 3.28 (2H, d, J=7.5 Hz), 3.51 (2H, t, J=7.5 Hz),3.64 (3H, s), 8.02 (1H, d, J=2.7 Hz), 8.32 (1H, d, J=2.7 Hz), 9.89 (1H,s).

REFERENCE EXAMPLE 14

To a solution of methyl4-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]butanoate (750 mg) indimethyl carbonate (20 ml) was added a 28% sodium methoxide solution inmethanol (810 mg), and the mixture was heated at 50° C. for 2 hoursunder a nitrogen atmosphere. The mixture was returned to roomtemperature, water was added thereto and then extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover magnesium sulfate. The solvent was distilled off under reducedpressure and the resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=6:1) togive methyl3-bromo-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate(654 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (6H, d, J=6.6 Hz), 2.01-2.13 (1H, m),2.83 (2H, t, J=3.9 Hz), 3.38 (2H, t, J=4.5 Hz), 3.52 (2H, d, J=7.5 Hz),3.80 (3H, s), 7.46 (1H, s), 7.61 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=2.4Hz).

REFERENCE EXAMPLE 15

A suspension of methyl3-bromo-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate(640 mg), 4-(2-butoxyethoxy)phenylboric acid (583 mg) and potassiumcarbonate (678 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred for 30 minutes under an argon atmosphere.Tetrakis(triphenylphosphine)palladium (110 mg) was added thereto, andthe mixture was heated at 115° C. for 6 hours under an argon atmosphere,which was allowed to cool. Water was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=19:1→hexane:ethyl acetate=4:1) to give methyl3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate(740 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.91-0.96 (9H, m), 1.30-1.45 (2H, m),1.55-1.70 (2H, m), 2.05-2.20 (1H, m), 2.86 (2H, t, J=4.5 Hz), 3.44 (2H,t, J=5.1 Hz), 3.55 (2H, t, J=6.3 Hz), 3.60 (2H, d, J=7.2 Hz), 3.79-3.82(5H, m), 4.16 (2H, t, J=4.8 Hz), 6.99 (2H, d, J=9.0 Hz), 7.44 (2H, d,J=9.0 Hz), 7.65 (1H, s), 7.70 (1H, d, J=2.4 Hz), 8.32 (1H, d, J=2.4 Hz).

REFERENCE EXAMPLE 16

To a solution of methyl3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate(720 mg) in THF (25 ml) and methanol (25 ml) was added a 1 N aqueoussodium hydroxide solution (6.4 ml), and the mixture was heated at 90° C.for 3 hours. After cooling to 0° C., water was added thereto, and themixture was neutralized with 1 N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was washed with hexane togive3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylicacid (654 mg) as yellow crystals.

m.p. 114.0-116.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.86-0.96 (9H, m), 1.34-1.46 (2H, m),1.57-1.66 (2H, m), 2.05-2.20 (1H, m), 2.83-2.93 (2H, m), 3.45-3.48 (2H,m), 3.55 (2H, t, J=6.6 Hz), 3.62 (2H, d, J=7.5 Hz), 3.81 (2H, t, J=5.1Hz), 4.16 (2H, t, J=5.1 Hz), 7.00 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0Hz), 7.71 (1H, d, J=2.4 Hz), 7.75 (1H, s), 8.35 (1H, d, J=2.4 Hz).

Elementary analysis: C₂₆H₃₄N₂O₄, Calcd. C, 71.21; H, 7.81; N, 6.39;Found. C, 70.91; H, 7.87; N, 6.07.

EXPERIMENTAL EXAMPLE

(1) Cloning of Human CCR5 Chemokine Receptor

Cloning of a CCR5 gene was conducted from human spleen cDNA by a PCRmethod. Using 0.5 ng of spleen cDNA (Toyobo Co., Ltd., QUICK-Clone cDNA)as a template, the PCR reaction was carried out in a DNA Thermal Cycler480 (Perkin Elmer) using a TaKaRa EX Taq (Takara Shuzo Co., Ltd.)(reaction conditions: 30 cycles of treatments at 95° C. for 1 minute, at60° C. for 1 minute, and at 75° C. for 5 minutes) by adding 25 pmol ofprimers, SEQ ID NO. 1 (sequence length: 34; sequence type: nucleic acid;number of chains: a single chain; topology: linear; sequence kind: othernucleic acid, synthetic DNA) described in Experimental Example (1) of WO99/32100, and SEQ ID NO. 2 (sequence length: 34; sequence type: nucleicacid; number of chains: a single chain; topology: linear; sequence kind:other nucleic acid, synthetic DNA) described in Experimental Example (1)of WO 99/32100, respectively, which were prepared by referring to thebase sequence of the CCR5 gene described by Samson et al. (Biochemistry35 (11), 3362-3367 (1996)). The PCR products were subjected to agarosegel electrophoresis to collect DNA fragments of about 1.0 kb. Then, theCCR5 gene was cloned using an Original TA Cloning Kit (Funakoshi Co.,Ltd.).

(2) Preparation of Plasmid for Expression of Human CCR5

The plasmids obtained above were digested with restriction enzymes XbaI(Takara Shuzo Co., Ltd.) and BamHI (Takara Shuzo Co., Ltd.), andsubjected to agarose gel electrophoresis to collect DNA fragments ofabout 1.0 kb. The DNA fragments and a plasmid pcDNA3.1 (Funakoshi Co.,Ltd.) for expression in animal cells, which was previously digested withXbaI and BamHI, were mixed and ligated by DNA Ligation Kit Ver.2 (TakaraShuzo Co., Ltd.). Transformation of E. coli JM109 competent cells(Takara Shuzo Co., Ltd.) gave plasmid pCKR5.

(3) Introduction of the Plasmid for Expression of Human CCR5 into CHO—K1Cells and Expression Thereof

CHO—K1 cells grown in a 750 ml tissue culture flask (Becton Dickinson)using Ham's F12 medium (Nihon Pharmaceutical Co., Ltd.) containing 10%fetal bovine serum (Lifetech Oriental) were collected from the flask byusing 0.5 g/L trypsin-0.2 g/L EDTA (Lifetech Oriental). The cells werethen washed with PBS (Lifetech Oriental), centrifuged (1000 rpm, 5minutes), and suspended in PBS. Next, DNA was introduced into the cellsusing Gene Pulser (Bio-Rad Laboratories Inc.) under the followingconditions. Namely, 8×10⁶ cells and 10 μg of plasmid pCKR5 forexpression of human CCR5 were added into a cuvette of a 0.4 cm-gap, andelectroporation was carried out at an electric voltage of 0.25 kV and acapacitance of 960 μF. Subsequently, the cells were transferred intoHam's F12 medium containing 10% fetal bovine serum, and incubated for 24hours. The cells were again collected, centrifuged, and then suspendedin Ham's F12 medium containing 10% fetal bovine serum and Geneticin(Lifetech Oriental) at a concentration of 500 μg/ml. The suspension ofcells was diluted to a concentration of 10⁴ cells/ml, and inoculated ona 96-well plate (Becton Dickinson) to give Geneticin-resistant strains.

Subsequently, the Geneticin-resistant strains were cultured in the96-well plate (Becton Dickinson), and then CCR5-expressing cells wereselected from the resistant strains. Namely, an assay buffer (Ham's F12medium containing 0.5% BSA, and 20 mM HEPES (Wako Pure ChemicalIndustries, Ltd., pH 7.2)) containing 200 pM [¹²⁵I]-RANTES (Amersham) asa ligand was added to each well and the binding reaction was carried outat room temperature for 40 minutes. Each well plate containing the cellswas washed with ice-cooled PBS, and then to each well was added 1 M NaOHin an amount of 50 μl/well, which was stirred. The cells to which theligand bound specifically, i.e., CCR5/CHO strains, were selected bymeasurement of radioactivity by γ-counter.

(4) Evaluation of Compound Based on CCR5 Antagonist Activity

The CCR5/CHO strains were inoculated on a 96-well microplate at aconcentration of 5×10⁴ cells/well, respectively and were cultured for 24hours. After the medium was removed by suction, to each well was addedan assay buffer containing a test compound (1 μM), and [¹²⁵I]-RANTES(Amersham) used as a ligand at a concentration of 100 pM. The reactionwas carried out at room temperature for 40 minutes. After the assaybuffer was removed by suction, each well plate containing the cells werewashed with ice-cooled PBS twice. Then, to each well was added 200 μl ofMicroScint-20 (Packard Industry Company, Inc.), and the radioactivitywas measured with TopCount (Packard Industry Company, Inc.).

According to the method above, inhibitory ratios to CCR5 binding of thetest compounds were determined. The results are shown in Table 1. TABLE1 Compound No. Binding Inhibitory Ratio (%) 1 94 2 93 3 100 4 100

FORMULATION EXAMPLE 1 Capsules

(1) (S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1- 40 mgpropyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (2) lactose 61 mg (3)microcrystalline cellulose 18 mg (4) magnesium stearate  1 mg contentsof 1 capsule 120 mg 

After mixing (1), (2), (3) and (4), the mixture is filled in gelatincapsules.

FORMULATION EXAMPLE 2 Capsules

(1) (S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1- 40 mgpropyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (2) lactose 61 mg (3)microcrystalline cellulose 18 mg (4) magnesium stearate  1 mg contentsof 1 capsule 120 mg 

After mixing (1), (2), (3) and (4), the mixture is filled in gelatincapsules.

FORMULATION EXAMPLE 3 Tablets

(1) (S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1- 40 mgpropyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (2) mannitol 51.2 mg   (3)microcrystalline cellulose 18 mg (4) hydroxypropyl cellulose 3.6 mg  (5)croscarmellose sodium  6 mg (6) magnesium stearate 1.2 mg  contents of 1tablet 120 mg 

(1), (2), (3) and (4) are mixed and granulated. To the granules areadded (5) and (6), and the mixture is compressed into tablets.

FORMULATION EXAMPLE 4 Tablets

(1) (S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1- 40 mgpropyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (2) mannitol 51.2 mg   (3)microcrystalline cellulose 18 mg (4) hydroxypropyl cellulose 3.6 mg  (5)croscarmellose sodium  6 mg (6) magnesium stearate 1.2 mg  contents of 1tablet 120 mg 

(1), (2), (3) and (4) are mixed and granulated. To the granules areadded (5) and (6), and the mixture is compressed into tablets.

INDUSTRIAL APPLICABILITY

The compound represented by the formula (I) or a salt thereof of thepresent invention has strong CCR5 antagonist activity and improvedsolubility in water, and thus can be advantageously used for preventionand treatment of a variety of human HIV infection, for example AIDS.

1. A compound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted; R³ is ahydrogen atom, a lower alkyl group which may be substituted or a loweralkoxy group which may be substituted; Z¹ is a 5- or 6-membered aromaticring which may be further substituted; Z² is a group represented by-Z^(2a)-W¹-Z^(2b)- wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted, or abond; and W¹ is an alkylene chain which may be substituted, analkenylene chain which may be substituted, or a bond; n is an integer of0 to 4; Y is O, S(O)_(p) (wherein p is 0, 1 or 2), CH₂ or NR⁴ (whereinR⁴ is a hydrogen atom, a hydrocarbon group which may be substituted, aheterocyclic group which may be substituted, or an acyl group which maybe substituted); and R² is (1) an amino group which may be substituted,in which the nitrogen atom may be converted to a quaternary ammonium oran oxide, (2) a nitrogen-containing heterocyclic group which may besubstituted and may contain a sulfur atom or an oxygen atom as aring-constituting atom, in which the nitrogen atom may be converted to aquaternary ammonium or an oxide, (3) a group represented by the formula:

wherein k is 0 or 1; when k is 0, the phosphorus atom may form aphosphonium salt; R⁵ and R⁶ are each a hydrocarbon group which may besubstituted, a hydroxy group which may be substituted or an amino groupwhich may be substituted; or R⁵ and R⁶ may be bonded to each other toform a ring with the adjacent phosphorus atom, (4) an amidino groupwhich may be substituted, or (5) a guanidino group which may besubstituted, or a salt thereof.
 2. A prodrug of the compound accordingto claim
 1. 3. The compound according to claim 1, wherein R¹ is abenzene, a furan, a thiophene, a pyridine, a cyclopentane, cyclohexane,a pyrrolidine, a piperidine, a piperazine, a morpholine, athiomorpholine or a tetrahydropyran, each of which may be substituted.4. The compound according to claim 1, wherein R¹ is a benzene which maybe substituted.
 5. The compound according to claim 1, wherein n is
 2. 6.The compound according to claim 1, wherein Z¹ is a benzene which may besubstituted with a substituent selected from (1) a halogen atom, (2) aC₁₋₄ alkyl group which may be substituted with a halogen atom, and (3) aC₁₋₄ alkoxy group which may be substituted with a halogen atom.
 7. Thecompound according to claim 1, wherein Z¹ is a benzene which may besubstituted with a methyl group or a trifluoromethyl group.
 8. Thecompound according to claim 1, wherein Z² is a group represented by-Z^(2a)-W²-Z^(2b)- wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted, or abond; and W² is an alkylene chain which may be substituted.
 9. Thecompound according to claim 1, wherein Z² is —CH₂—, —CH(OH)—, or—S(O)_(m)—CH₂— (wherein m is 0, 1 or 2).
 10. The compound according toclaim 1, wherein Z² is a group represented by —S(O)_(m)—CH₂— (wherein mis 0, 1 or 2).
 11. The compound according to claim 1, wherein R² is (1)an amino group which may be substituted, in which the nitrogen atom maybe converted to a quaternary ammonium or an oxide, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide, (3) an amidino group which may be substituted, or (4) a guanidinogroup which may be substituted.
 12. The compound according to claim 1,wherein R² is an amino group which may be substituted, or anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom. 13.The compound according to claim 1, wherein R² is represented by theformula —NRR′ (wherein R and R′ are each an aliphatic hydrocarbon groupwhich may be substituted, or an alicyclic heterocyclic group which maybe substituted).
 14. The compound according to claim 1, wherein R² is anitrogen-containing aromatic heterocyclic group which may besubstituted.
 15. The compound according to claim 1, wherein R² is animidazolyl group which may be substituted or a triazolyl group which maybe substituted.
 16. The compound according to claim 1, wherein R¹ is abenzene, a furan, a thiophene, a pyridine, a cyclopentane, acyclohexane, a pyrrolidine, a piperidine, a piperazine, a morpholine, athiomorpholine or a tetrahydropyran, each of which may be substitutedwith a halogen, a nitro, a cyano, a C₁₋₆ alkyl, a C₁₋₆ alkoxy, a C₁₋₆alkoxy-C₁₋₆ alkyl or a C₁₋₆ alkoxy-C₁₋₆ alkoxy, a Y-containing ring is a7- to 10-membered ring which may contain an oxygen atom, a nitrogen atomor a sulfur atom which may be oxidized, as a ring-constituting atom, andmay have, as a substituent, an alkyl which may be substituted, analkenyl which may be substituted, an aryl which may be substituted, aheterocyclic group which may be substituted or formyl, Z¹ is a benzenewhich may be substituted with substituent(s) selected from (1) a halogenatom, (2) a C₁₋₄ alkyl group which may be substituted with halogenatom(s) and (3) a C₁₋₄ alkoxy group which may be substituted withhalogen atom(s), Z² is Z^(2a)W-Z^(2b)- wherein Z^(2a) and Z^(2b) areeach O, S(O)_(m) (wherein m is 0, 1 or 2), an imino group which may besubstituted with a C₁₋₄ alkyl group or a bond, and W¹ is a bond, or aC₁₋₄ alkylene chain or a C₂₋₄ alkenylene chain, each of which may have,as a substituent, a C₁₋₆ alkyl, a hydroxy group, a hydroxyimino or aC₁₋₆ alkoxyimino, and R² is an amino group which may be substituted witha C₁₋₄ alkyl group, or a nitrogen-containing heterocyclic group whichmay contain a sulfur atom or an oxygen atom as a ring-constituting atomand may be substituted with a C₁₋₄ alkyl group.
 17. A compoundrepresented by the formula:

wherein R^(1a) is a (C₁₋₆ alkoxy-C₁₋₆alkoxy)phenyl; R^(2a) is (1) anN—C₁₋₆ alkyl-N-tetrahydropyranylamino, (2) an imidazolyl which may besubstituted with a C₁₋₆ alkyl which may be substituted, or (3) atriazolyl which may be substituted with a C₁₋₆ alkyl which may besubstituted; R³ is a hydrogen atom, a lower alkyl group which may besubstituted or a lower alkoxy group which may be substituted; Y^(a) is(1) an oxygen atom, (2) S(O)_(p) (wherein p is 0, 1 or 2), (3) CH₂ or(4) an imino group which may have, as a substituent, a formyl, a C₁₋₆alkyl which may be substituted, a C₂₋₆ alkenyl which may be substituted,an aryl which may be substituted, a heterocyclic group which may besubstituted, an arylmethyl which may be substituted or a heterocyclicmethyl which may be substituted; n′ is 1, 2 or 3; na is 0 or 1; andZ^(2a) is a bond, S, SO or SO₂, or a salt thereof.
 18. The compoundaccording to claim 17, wherein Z^(2a) is SO.
 19. The compound accordingto claim 18, wherein Z^(2a) is SO having a configuration of (S).
 20. Thecompound according to claim 17, wherein Y^(a) is an imino group whichmay have, as a substituent, a formyl, a C₁₋₆ alkyl which may besubstituted, a alkenyl which may be substituted, an aryl which may besubstituted, a heterocyclic group which may be substituted, anarylmethyl which may be substituted or a heterocyclic methyl which maybe substituted. 21.(S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide.22.(S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide.23. A process for producing a compound represented by the formula:

wherein R^(2″) is (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as a ring-constituting atom, inwhich the nitrogen atom may be converted to a quaternary ammonium, or(3) a group represented by the formula:

wherein k is 0 or 1; when k is 0, the phosphorus atom may form aphosphonium salt; R⁵ and R⁶ are each a hydrocarbon group which may besubstituted, a hydroxy group which may be substituted or an amino groupwhich may be substituted; and R⁵ and R⁶ may be bonded to each other toform a ring with the adjacent phosphorus atom; and the other symbolshave the same meanings as defined in claim 1, or a salt thereof, whichcomprises subjecting a compound represented by the formula:

wherein each symbol has the same meaning as defined in claim 1, or asalt thereof or a reactive derivative thereof, and a compoundrepresented by the formula:H₂N-Z¹-Z²-R^(2″) wherein Z¹ and Z² have the same meaning as defined inclaim 1 are and R^(2″) has the same meaning as defined above, or saltthereof, to a condensation reaction, and then optionally to adeprotection reaction, an oxidation/reduction reaction and/or aquaternization reaction.
 24. A pharmaceutical composition comprising acompound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted; R³ is ahydrogen atom, a lower alkyl group which may be substituted or a loweralkoxy group which may be substituted; Z¹ is a 5- or 6-membered aromaticring which may be further substituted; Z² is a group represented by-Z^(2a)-W¹-Z^(2b)- wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted, or abond; and W¹ is an alkylene chain which may be substituted, analkenylene chain which may be substituted, or a bond; n is an integer of1 to 4; Y is O, S(O)_(p) (wherein p is 0, 1 or 2), CH₂ or NR⁴ (whereinR⁴ is a hydrogen atom, a hydrocarbon group which may be substituted, aheterocyclic group which may be substituted, or an acyl group which maybe substituted); and R² is (1) an amino group which may be substituted,in which the nitrogen atom may be converted to a quaternary ammonium oran oxide, (2) a nitrogen-containing heterocyclic group which may besubstituted and may contain a sulfur atom or an oxygen atom as aring-constituting atom, in which the nitrogen atom may be converted to aquaternary ammonium or an oxide, (3) a group represented by the formula:

wherein k is 0 or 1; when k is 0, the phosphorus atom may form aphosphonium salt; R⁵ and R⁶ are each a hydrocarbon group which may besubstituted, a hydroxy group which may be substituted or an amino groupwhich may be substituted; and R⁵ and R⁶ may be bonded to each other toform a ring with the adjacent phosphorus atom, (4) an amidino groupwhich may be substituted, or (5) a guanidino group which may besubstituted, a salt thereof or a prodrug thereof.
 25. The pharmaceuticalcomposition according to claim 24, which is a CCR antagonist.
 26. Thepharmaceutical composition according to claim 25, wherein CCR is CCR5and/or CCR2.
 27. The pharmaceutical composition according to claim 25,wherein CCR is CCR5.
 28. The pharmaceutical composition according toclaim 24, which is a prophylactic and/or therapeutic agent for HIVinfection, chronic rheumatoid arthritis, autoimmune diseases, allergicdiseases, ischemic brain cell disorder, cardiac infarction,nephritis/nephropathy, arteriosclerosis or graft-versus-host diseases.29. The pharmaceutical composition according to claim 24, which is aprophylactic and/or therapeutic agent for HIV infection.
 30. Thepharmaceutical composition according to claim 24, which is aprophylactic and/or therapeutic agent for AIDS.
 31. The pharmaceuticalcomposition according to claim 24, which is a suppressive agent fordisease progression of AIDS.
 32. A method for preventing or treating HIVinfection, chronic rheumatoid arthritis, autoimmune diseases, allergicdiseases, ischemic brain cell disorder, cardiac infarction,nephritis/nephropathy, arteriosclerosis or graft-versus-host diseases,which comprises administering an effective amount of the compoundaccording to claim 1, a salt thereof or a prodrug thereof, to a subjectin need thereof.
 33. Use of the compound according to claim 1, a saltthereof or a prodrug thereof, for manufacturing a prophylactic and/ortherapeutic agent for HIV infection, chronic rheumatoid arthritis,autoimmune diseases, allergic diseases, ischemic brain cell disorder,cardiac infarction, nephritis/nephropathy, arteriosclerosis orgraft-versus-host diseases.